US4496745A - Epoxycarbacyclin derivatives, their preparation and use - Google Patents
Epoxycarbacyclin derivatives, their preparation and use Download PDFInfo
- Publication number
- US4496745A US4496745A US06/545,097 US54509783A US4496745A US 4496745 A US4496745 A US 4496745A US 54509783 A US54509783 A US 54509783A US 4496745 A US4496745 A US 4496745A
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- United States
- Prior art keywords
- group
- methylene
- epoxy
- methyl
- acid
- Prior art date
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- 238000002360 preparation method Methods 0.000 title abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 157
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 32
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 25
- 150000002148 esters Chemical class 0.000 claims abstract description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 9
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 claims abstract description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 5
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims description 241
- -1 3-methylcyclopentyl Chemical group 0.000 claims description 209
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 13
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 10
- 125000006024 2-pentenyl group Chemical group 0.000 claims description 9
- 125000006042 4-hexenyl group Chemical group 0.000 claims description 9
- 125000006043 5-hexenyl group Chemical group 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 6
- 239000005977 Ethylene Substances 0.000 claims description 6
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims description 6
- 150000004702 methyl esters Chemical class 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 125000005907 alkyl ester group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 4
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 2
- 125000004494 ethyl ester group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 159000000001 potassium salts Chemical class 0.000 claims description 2
- 101100434170 Oryza sativa subsp. japonica ACR2.1 gene Proteins 0.000 claims 1
- 101100434171 Oryza sativa subsp. japonica ACR2.2 gene Proteins 0.000 claims 1
- 150000002431 hydrogen Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 62
- XZFRIPGNUQRGPI-WLPVIMDJSA-N Carbacyclin Chemical class C1\C(=C\CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 XZFRIPGNUQRGPI-WLPVIMDJSA-N 0.000 abstract description 6
- 239000000543 intermediate Substances 0.000 abstract description 5
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 abstract 1
- 101150035983 str1 gene Proteins 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 238000000034 method Methods 0.000 description 47
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 46
- 239000000203 mixture Substances 0.000 description 36
- 238000000862 absorption spectrum Methods 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- 239000002904 solvent Substances 0.000 description 32
- 239000007788 liquid Substances 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 23
- 125000001424 substituent group Chemical group 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 239000000047 product Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000002585 base Substances 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 229910052744 lithium Inorganic materials 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 12
- 229910052783 alkali metal Inorganic materials 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 150000001340 alkali metals Chemical group 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- 239000012442 inert solvent Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 150000002596 lactones Chemical class 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- WGJJROVFWIXTPA-OALUTQOASA-N prostanoic acid Chemical class CCCCCCCC[C@H]1CCC[C@@H]1CCCCCCC(O)=O WGJJROVFWIXTPA-OALUTQOASA-N 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 6
- BUBVLQDEIIUIQG-UHFFFAOYSA-N 3,4,5-tris(phenylmethoxy)-6-(phenylmethoxymethyl)oxan-2-one Chemical compound C=1C=CC=CC=1COC1C(OCC=2C=CC=CC=2)C(OCC=2C=CC=CC=2)C(=O)OC1COCC1=CC=CC=C1 BUBVLQDEIIUIQG-UHFFFAOYSA-N 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 125000003107 substituted aryl group Chemical group 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 4
- 150000008041 alkali metal carbonates Chemical class 0.000 description 4
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 125000000547 substituted alkyl group Chemical group 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 3
- 229910003002 lithium salt Inorganic materials 0.000 description 3
- 159000000002 lithium salts Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 238000000039 preparative column chromatography Methods 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- AEBWATHAIVJLTA-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydropentalene Chemical compound C1CCC2CCCC21 AEBWATHAIVJLTA-UHFFFAOYSA-N 0.000 description 2
- 125000006055 1-methyl-4-pentenyl group Chemical group 0.000 description 2
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 2
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 2
- 125000006053 2-methyl-3-pentenyl group Chemical group 0.000 description 2
- 125000005916 2-methylpentyl group Chemical group 0.000 description 2
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 2
- 125000003119 4-methyl-3-pentenyl group Chemical group [H]\C(=C(/C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000004133 Sodium thiosulphate Substances 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- XGRJZXREYAXTGV-UHFFFAOYSA-N chlorodiphenylphosphine Chemical compound C=1C=CC=CC=1P(Cl)C1=CC=CC=C1 XGRJZXREYAXTGV-UHFFFAOYSA-N 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000004953 trihalomethyl group Chemical group 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 description 1
- 150000000180 1,2-diols Chemical class 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JQCSUVJDBHJKNG-UHFFFAOYSA-N 1-methoxy-ethyl Chemical group C[CH]OC JQCSUVJDBHJKNG-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- JKTYGPATCNUWKN-UHFFFAOYSA-N 4-nitrobenzyl alcohol Chemical compound OCC1=CC=C([N+]([O-])=O)C=C1 JKTYGPATCNUWKN-UHFFFAOYSA-N 0.000 description 1
- 101100177155 Arabidopsis thaliana HAC1 gene Proteins 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 101150108015 STR6 gene Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- RZSMSXXOYMFIKN-UHFFFAOYSA-N bromo(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(Br)C1=CC=CC=C1 RZSMSXXOYMFIKN-UHFFFAOYSA-N 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- BJBXRRHIBSXGLF-UHFFFAOYSA-N chloro-bis(4-methylphenyl)phosphane Chemical compound C1=CC(C)=CC=C1P(Cl)C1=CC=C(C)C=C1 BJBXRRHIBSXGLF-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 125000006351 ethylthiomethyl group Chemical group [H]C([H])([H])C([H])([H])SC([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000006352 iso-propylthiomethyl group Chemical group [H]C([H])([H])C([H])(SC([H])([H])*)C([H])([H])[H] 0.000 description 1
- 150000002641 lithium Chemical class 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
- C07C405/0075—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system
- C07C405/0083—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system which is only ortho or peri condensed, e.g. carbacyclins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a series of new epoxycarbacyclin derivatives, and provides a process for preparing these derivatives from Z-isomers of corresponding carbacyclin compounds and a process for converting these derivatives to the E-isomers of the corresponding carbocyclin compounds.
- the two processes of the invention enable the Z-isomer of a carbacyclin compound to be converted to its corresponding E-isomer in good yield.
- Carbacyclin compounds are chemically stable and have been developed for various therapeutic uses, including the treatment of thrombosis.
- the compounds are produced by chemical synthesis and are normally obtained as mixtures of the E- and Z-isomers with respect to the exo double bond of the compound.
- U.S. Pat. No. 4,322,435 discloses a series of carbacyclin derivatives, many of which have a double bond at the 5-position; during the synthesis of these compounds, the product is usually obtained as a mixture of the 5E- and 5Z-isomers.
- the 5E-isomer is much more active and useful than its corresponding 5Z-isomer, which may have so little activity as to be of no practical use.
- the present invention provides epoxycarbacyclin derivatives of formula (I): ##STR2## (in which: R 1 and R 2 are the same or different and each represents hydrogen or a hydroxy-protecting group;
- R 3 represents an alkyl group having from 1 to 12 carbon atoms which is optionally substituted, an alkenyl group having from 2 to 12 carbon atoms, an alkynyl group having from 2 to 6 carbon atoms or a cycloalkyl group which is optionally substituted;
- X represents an ethylene group, a trans-vinylene group or an ethynylene group
- the invention also provides a process for preparing compounds of formula (I), as defined above, and their salts and esters, which comprises reacting a 5Z-carbacyclin derivative of formula (II): ##STR3## (in which R 1 , R 2 , R 3 and X are as defined above) with iodine and with an alkali metal iodide in the presence of a base to give a lactone of formula (III): ##STR4## (in which R 1 , R 2 , R 3 and X are as defined above) and reacting said lactone of formula (III) with water or an alcohol, to give said compound of formula (I), and, if necessary, salifying or esterifying said compound of formula (I).
- the invention further provides a process for preparing a 5E-carbacyclin derivative of formula (V): ##STR5## (in which R 1 , R 2 , R 3 and X are as defined above) and salts and esters thereof, which comprises reacting an epoxycarbacyclin derivative of formula (I), defined above, or a salt or ester thereof with a phosphorus compound of formula (VI): ##STR6## (in which R 5 and R 6 are the same or different and each represents an alkyl group having from 1 to 6 carbon atoms, an aralkyl group or an aryl group and M represents an alkali metal atom) and then treating the product with a compound of formula (VII):
- R 7 represents an alkyl group having from 1 to 4 carbon atoms, or an aralkyl group and Q represents a halogen atom, an alkanesulphonyloxy group or an arylsulphonyloxy group
- Q represents a halogen atom, an alkanesulphonyloxy group or an arylsulphonyloxy group
- the invention provides a process for converting a 5Z-carbacyclin derivative of formula (II) to its corresponding 5E-carbacyclin compound of formula (V) by preparing said epoxycarbacyclin derivative of formula (I) or a salt or ester thereof from said 5Z-carbacyclin derivative of formula (II), by the first-mentioned process of the invention and then converting said epoxycarbacyclin derivative of formula (I) or salt or ester thereof to said 5E-carbacyclin derivative of formula (V) or a salt or ester thereof by the second-mentioned process of the invention.
- the compounds of the invention can exist in the form of various geometric isomers and other stereoisomers, particularly with respect to the double ring system.
- Preferred isomers of the compounds of formula (I) are those of formula (Ia): ##STR7## (in which R 1 , R 2 , R 3 and X are as defined above) and the salts and esters preferably have a corresponding configuration.
- compounds of formulae (II), (III) and (V) preferably have an equivalent configuration, e.g. compounds of formula (Va): ##STR8## (in which R 1 , R 2 , R 3 and X are as defined above), the salts and esters preferably having a corresponding configuration.
- R 1 and R 2 may be the same or different and each represents a hydrogen atom or a hydroxy-protecting group. Although R 1 and R 2 may be different, we prefer that either both should be hydrogen atoms or both should be hydroxy-protecting groups. Where both R 1 and R 2 represent hydroxy-protecting groups, these likewise may be the same or different, but it is generally more convenient if the two hydroxy-protecting groups represented by R 1 and R 2 are the same. In general, prior to any therapeutic use of the compounds, any hydroxy-protecting groups represented by R 1 and R 2 will be removed from the compound.
- One preferred class of hydroxy-protecting groups comprises substituted C 1 -C 4 alkyl groups having a C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, trihalomethyl or aralkyloxy substituent at the ⁇ -position; specific examples include the methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, benzyloxymethyl, p-nitrobenzyloxymethyl, p-bromobenzyloxymethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 1-methoxyethyl, 1-ethoxyethyl, 1-methoxy-1-methylethyl or 1-ethyl-1-methoxyethyl groups.
- substituent on the alkyl group is an alkoxy, alkylthio or aralkyloxy group
- this substituent may itself be substituted, the substituents being, for example, those suggested as substituents for the alkyl group or they may be alkyl groups.
- An example of such a substituted group is the 2-methoxyethoxymethyl group.
- R 1 or R 2 include aryl groups, i.e.
- the hydroxy-protecting group represented by R 1 or R 2 is an aralkyl group; examples of such aralkyl groups include the benzyl, p-nitrobenzyl, p-bromobenzyl, 1-methyl-1-phenylethyl, 1-ethyl-1-phenylethyl, diphenylmethyl and trityl (triphenylmethyl) groups.
- hydroxy-protecting groups which may be represented by R 1 and/or R 2 include heterocyclic groups, such as the 4-methoxytetrahydrothiopyran-4-yl group and groups of formula ##STR9## (in which n is an integer of from 3 to 5).
- R 1 and/or R 2 include trialkylsilyl, dialkylphenylsilyl and diphenylalkylsilyl groups, in which the or each alkyl group has from 1 to 4 carbon atoms.
- examples of such groups include the trimethylsilyl, triethylsilyl, dimethylisopropylsilyl, t-butyl-dimethylsilyl, dimethylphenylsilyl and diphenyl-t-butylsilyl groups.
- hydroxy-protecting groups which may be represented by R 1 and/or R 2 include acyl groups, especially carboxylic acyl groups and most preferably alkanoyl or arylcarbonyl groups, such as the acetyl, propionyl, butyryl, benzoyl and p-methylbenzoyl groups.
- any hydroxy-protecting group may be employed in this position, provided that it may be introduced and removed without substantially affecting the remainder of the molecule.
- Preferred hydroxy-protecting groups represented by R 1 and R 2 include: substituted C 1 -C 4 alkyl groups having one or more C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, trihalomethyl or aralkyloxy, substituents at the ⁇ -position; the 2-methoxyethoxymethyl group; the tetrahydrofuran-2-yl group; the tetrahydropyran-2-yl group; the 4-methoxytetrahydrothiopyran-4-yl group; a trialkylsilyl or dialkylphenylsilyl group in which each alkyl group has from 1 to 4 carbon atoms; the acetyl group; the propionyl group; or the benzoyl group.
- Particularly preferred hydroxy-protecting groups which may be represented by R 1 and/or R 2 are the methoxymethyl, tetrahydropyran-2-yl, t-butyldimethylsilyl, acetyl and benzoyl groups.
- R 3 represents an optionally substituted C 1 -C 12 alkyl group, a C 2 -C 12 alkenyl group, a C 2 -C 6 alkynyl group or an optionally substituted cycloalkyl group.
- R 3 represents an optionally substituted alkyl group
- the alkyl group which may be a straight or branched chain group, may be, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, 1-methylpentyl, 2-methylpentyl, hexyl, heptyl, 1,1-dimethylpentyl, 1-methylhexyl, 2-methylhexyl, 2-ethylpentyl, octyl, 2-methyloctyl, nonyl, 2-methylnonyl, 2-ethyloctyl, decyl, 2-methyldecyl or 2-ethyldecyl group.
- alkyl group represented by R 3 for example halogen atoms, alkoxy groups, optionally substituted cycloalkyl groups, optionally substituted aryl groups and groups of formula --Y--A (in which Y represents an oxygen or sulphur atom or an --NH group and A represents an optionally substituted aryl group).
- R 3 represents an unsubstituted alkyl group or a substituted alkyl group having a halogen or alkoxy substituent
- the alkyl group is preferably a C 4 -C 10 alkyl group, for example a butyl, isobutyl, pentyl, isopentyl, 1-methylpentyl, 2-methylpentyl, hexyl, heptyl, 1,1-dimethylpentyl, 1-methylhexyl, 2-methylhexyl, 2-ethylpentyl, octyl, 2-methyloctyl or 2-ethyloctyl group, more preferably a pentyl, 1-methylpentyl, hexyl, 1,1-dimethylpentyl, 1-methylhexyl or 2-methylhexyl group.
- R 3 represents a substituted alkyl group having an optionally substituted cycloalkyl, optionally substituted aryl or --Y--A substituent
- the alkyl group preferably has from 1 to 3 carbon atoms, i.e. a methyl, ethyl, propyl or isopropyl group, more preferably a methyl or ethyl group.
- substituent on the alkyl group represented by R 3 is a halogen atom, this is preferably a fluorine, chlorine or bromine atom.
- substituent on the alkyl group represented by R 3 is an alkoxy group, it is preferably a C 1 -C 4 alkoxy group, which may be a straight or branched chain group, for example a methoxy, ethoxy, propoxy, isopropoxy or butoxy group.
- R 3 represents a cycloalkyl group or a substituted alkyl group having an optionally substituted cycloalkyl substituent
- the cycloalkyl group preferably has from 3 to 7 ring carbon atoms and examples include the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.
- substituents on these cycloalkyl groups include: halogen atoms, such as fluorine, chlorine or bromine atoms; alkyl groups having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl and butyl groups; and the trifluoromethyl group; preferred substituents are the methyl and ethyl groups.
- the cycloalkyl group is a substituent on an alkyl group represented by R 3 , it is preferably a cyclopentyl or cyclohexyl group, which may be unsubstituted or may have one or more substituents as noted above.
- the cycloalkyl group itself it is preferably a cyclohexyl, cyclopentyl or 1-butylcyclopropyl group.
- substituent on the alkyl group represented by R 3 is an optionally substituted aryl group or a group of formula --Y--A.
- a representing an optionally substituted aryl group the aryl group is preferably a phenyl or naphthyl group, more preferably a phenyl group. This aryl group may be substituted or unsubstituted; where it is substituted, examples of suitable substituents are the same as those given as substituents for cycloalkyl groups in the preceding paragraph.
- substituent on the alkyl group represented by R 3 is a group of formula --Y--A.
- Y may represent an oxygen atom, a sulphur atom or an --NH group, preferably an oxygen atom or a sulphur atom.
- substituents on the alkyl group represented by R 3 include the fluorine atom and methoxy, ethoxy, cyclopentyl, 3-methylcyclopentyl, 3-ethylcyclopentyl, cyclohexyl, 3-methylcyclohexyl, 3-ethylcyclohexyl, phenyl, m-chlorophenyl, phenoxy, phenylthio and p-trifluoromethylphenoxy groups.
- R 3 represents an alkenyl group, it is a group having from 2 to 12 carbon atoms and may be a straight or branched chain group.
- examples of such groups include the vinyl, allyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 4-hexenyl, 5-hexenyl, 1,4-dimethyl-3-pentenyl, 5-heptenyl, 6-methyl-5-heptenyl, 2,6-dimethyl-5-heptenyl, 1,1,6-trimethyl-5-heptenyl, 6-methyl-5-octenyl, 2,6-dimethyl-5-octenyl, 6-ethyl-5-octenyl, 2-methyl-6-ethyl-5-octenyl and 2,6-diethyl-5-octenyl groups.
- alkenyl groups having from 4 to 12 carbon atoms for example the 2-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 4-hexenyl, 5-hexenyl, 1,4-dimethyl-3-pentenyl, 5-heptenyl, 6-methyl-5-heptenyl, 2,6-dimethyl-5-heptenyl, 1,1,6-trimethyl-5-heptenyl, 6-methyl-5-octenyl, 2,6-dimethyl-5-octenyl, 6-ethyl-5-octenyl, 2-methyl-6-ethyl-5-octenyl and 2,6-diethyl-5-octenyl groups, more preferably the 2-pentenyl, 4-pentenyl, 4-hexenyl, 5-hexenyl, 6-methyl-5-heptenyl and 2,6-dieth
- R 3 represents an alkynyl group having from 2 to 6 carbon atoms, it may be a straight or branched chain group; examples include the ethynyl, propargyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 1-methyl-2-pentynyl and 1-methyl-3-pentynyl groups, of which we prefer the alkynyl groups having from 4 to 6 carbon atoms such as the 2-butynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-pentynyl and 1-methyl-3-pentynyl groups, most preferably the 1-methyl-3-pentynyl group.
- X which may represent an ethylene, trans-vinylene or ethynylene group, is preferably an ethylene or trans-vinylene group.
- the compound of the invention is an ester, it is preferably a C 1 -C 4 alkyl ester or an aralkyl ester.
- Particularly preferred compounds of formula (I) are, accordingly, those of formula (Ib), whilst particularly preferred compounds of formula (V) are those of formula (Vb): ##STR10## (in which R 1 , R 2 , R 3 and X are as defined above and R 4 represents a hydrogen atom, a C 1 -C 4 alkyl group or an aralkyl group).
- C 1 -C 4 alkyl groups which may be represented by R 4 in the compounds of formulae (Ib) and (Vb) and which may be the ester moiety of esters of compounds of formulae (I) and (V) include straight or branched chain groups, preferably a methyl, ethyl, propyl, isopropyl or butyl group, more preferably a methyl or ethyl group.
- aralkyl groups which may be represented by R 4 or may be the aforesaid ester moiety include the benzyl, p-bromobenzyl and p-nitrobenzyl groups, more preferably the benzyl group.
- Particularly preferred classes of compound of formula (I), (Ia) and (Ib) are as follows:
- R 1 and R 2 are the same or different and each represents a hydrogen atom or a hydroxy-protecting group
- R 3 represents a C 4 -C 10 alkyl group which is unsubstituted or which has one or more fluorine, methoxy or ethoxy substituents; a C 1 -C 3 alkyl group having one or more cyclopentyl, 3-methylcyclopentyl, 3-ethylcyclopentyl, cyclohexyl, 3-methylcyclohexyl, 3-ethylcyclohexyl, phenyl, p-trifluoromethylphenoxy, phenoxy, phenylthio or p-tolyloxy substituents; a C 4 -C 12 alkenyl group; a C 4 -C 6 alkynyl group; a cyclopentyl group; a 3-methylcyclopentyl group; a 3-ethylcyclopentyl group; a cyclohexyl group; a 3-methylcyclohexyl group; or a 3-ethylcyclohexy
- X represents an ethylene, trans-vinylene or ethynylene group
- R 3 and X are as defined for class (A) and in which R 1 and R 2 are the same or different and each represents: a hydrogen atom; a C 1 -C 4 alkyl group having at its ⁇ -position a C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, aralkyloxy or trihalomethyl substituent; a 2-methoxyethoxymethyl group; a tetrahydrofuran-2-yl group; a tetrahydropyran-2-yl group; a 4-methoxytetrahydrothiopyran-4-yl group; a trialkylsilyl or dialkylphenylsilyl group, in which each alkyl group has from 1 to 4 carbon atoms; an acetyl group; a propionyl group; or a benzoyl group;
- R 1 and R 2 are the same or different and each represents a hydrogen atom or a methoxymethyl, tetrahydropyran-2-yl, t-butyl-dimethylsilyl, acetyl or benzoyl group;
- R 3 represents a pentyl, 1-methylpentyl, hexyl, 1-methylhexyl, 1,1-dimethylpentyl, 2-methylhexyl, 2-ethoxy-1,1-dimethylethyl, 5-methoxypentyl, 5-methoxy-1-methylpentyl, 1-fluoropentyl, cyclopentylmethyl, 3-methylcyclopentylmethyl, 2-cyclopentylethyl, 2-cyclopentyl-1-methylethyl, cyclohexylmethyl, 3-ethylcyclohexylmethyl, 2-cyclohexylethyl, benzyl, phenethyl, p-methylbenzyl, phenoxymethyl, m-chlorophenoxymethyl, phenylthiomethyl, 2-pentenyl, 4-pentenyl, 4-hexenyl, 5-hexenyl, 6-methyl-5-heptenyl, 2,6-dimethyl-5-
- X represents an ethylene or trans-vinylene group
- R 1 and R 2 are the same or different and each represents a hydrogen atom, a tetrahydropyran-2-yl group, a t-butyl-dimethylsilyl group or an acetyl group;
- R 3 represents a pentyl, 1-methylhexyl, 1,1-dimethylpentyl, 5-methoxypentyl, phenoxymethyl, 2-pentenyl, 4-pentenyl, 4-hexenyl, 5-hexenyl, 6-methyl-5-heptenyl, 2,6-dimethyl-5-heptenyl, 1-methyl-3-pentynyl or cyclopentyl group; and
- X represents a trans-vinylene group
- the compounds of the invention are named as derivatives of prostanoic acid.
- the nomenclature is based upon compounds in which R 3 represents a C 5 group and the numbering system employed is as shown on the following skeletal structure: ##STR11##
- the compounds listed above are the free acids, i.e. compounds of formula (I).
- particularly preferred compounds are Compounds No. 3, 4, 6, 23, 40, 41, 52, 53, 95, 96, 107, 112, 114, 116, 121, 123, 133, 135 and 161 of which Compounds No. 3, 4, 40, 52 and 161 are most preferred.
- the compounds of formula (I) and salts and esters thereof may be prepared by what is effectively a 2-step process, in the first step of which the compound of formula (II): ##STR12## (in which R 1 , R 2 , R 3 and X are as defined above) is converted to a lactone of formula (III): ##STR13## (in which R 1 , R 2 , R 3 and X are as defined above) and in the second step of which this lactone is converted to the desired compound of formula (I) or, depending upon reaction conditions and reagents, to a salt or ester thereof. If desired, these steps may be followed by salification or esterification.
- the 5Z-carbacyclin compound of formula (II) is reacted with iodine and an alkali metal iodide in the presence of a base and preferably in a solvent.
- the starting material, the compound of formula (II), may be prepared, for example, by the processes described in British patent specification No. 2,012,265.
- the molar ratio of iodine to compound of formula (II) is preferably from 1:1 to 2:1.
- Suitable solvents include: water; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, benzyl alcohol or p-nitrobenzyl alcohol; ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or diglyme; amides such as dimethylformamide or dimethylacetamide; sulphoxides such as dimethyl sulphoxide; and mixtures of any two or more thereof. Of these, alcohols are preferred.
- Suitable bases include: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide or barium hydroxide; alkali metal carbonates such as sodium carbonate or potassium carbonate; alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide or potassium t-butoxide. Of these, we prefer to use alkali metal carbonates or alkali metal bicarbonates.
- the molar ratio of base to compound of formula (II) is preferably from 1:1 to 4:1.
- alkali metal iodides examples include lithium iodide, sodium iodide and potassium iodide, of which potassium iodide is preferred.
- a large excess of the iodide is preferably employed, for example a molar ratio of iodide to compound of formula (II) of from 1:1 to 10:1.
- the reaction temperature is not critical and, accordingly, for convenience the reaction is preferably carried out at ambient temperature. At such a temperature, the time required for the reaction will, depending upon the reactants and other reaction conditions, generally be within the range from 2 hours to 15 hours.
- the second step of this reaction sequence comprises reacting the lactone of formula (III) with water or an alcohol, preferably with a compound of formula (IV):
- a base in which R 4 is as defined above
- suitable bases include those described in relation to the first step; where R 4 represents a hydrogen atom, the base is most preferably an alkali metal hydroxide or an alkali metal carbonate; when R 4 represents an alkyl group or an aralkyl group, the base is most preferably an alkali metal carbonate or an alkali metal alkoxide.
- suitable solvents include those already given for the first step.
- the compound of formula (IV) or other alcohol may serve as or as part of the solvent.
- R 4 represents a hydrogen atom
- the compound of formula (IV) is water and, accordingly, the solvent employed for this step may be water or a mixture of water with the solvent employed for the first step.
- R 4 represents an alkyl or aralkyl group
- the compound of formula (IV) is an alcohol and, accordingly, if an excess of this alcohol is employed, then the alcohol itself may serve as the solvent.
- the temperature at which the reaction of the second step is carried out is not particularly critical and, accordingly, for convenience we prefer to carry out the reaction at about ambient temperature. At such a temperature, depending upon the reagents and other reaction conditions, the time required for the reaction will generally be within the range from 1 hour to 5 hours.
- a compound of formula (I) itself has been prepared by the above sequence of reactions, this may, if desired, be converted to the corresponding compound in which R 4 represents an alkyl group or an aralkyl group by conventional esterification methods, for example by reacting the compound of formula (I) with a diazoalkane, or by converting said compound of formula (I) to its corresponding acid halide and then treating this acid halide with an alcohol of formula R 4 OH.
- R 1 represents a hydrogen atom by conventional deesterification techniques, although this is, in general, less preferred.
- the compounds may be salified, if necessary, to prepare any desired salt.
- the desired product may be recovered from the reaction mixture by conventional means.
- one suitable recovery technique comprises: pouring the reaction mixture into water; if necessary, treating the resulting mixture with a reducing agent or acidifying it with dilute hydrochloric acid; extracting the mixture with a water-immiscible organic solvent; drying the organic extract; and finally distilling the solvent from the extract to give the desired product.
- This product may, if necessary, be further purified by such conventional techniques as recrystallisation, preparative thin layer chromatography or column chromatography.
- the intermediate lactone compound of formula (III) obtained in the course of the above reaction sequence may be isolated and purified from the reaction mixture obtained in the first step; however, in general, it is more convenient to carry out the two steps of the above reaction sequence without intermediate isolation of the compound of formula (III).
- Compounds of formula (I) can be converted to 5E-carbacyclin derivatives having potent pharmaceutical activity.
- This step is preferably carried out as a third step in the reaction sequence which starts with the preparation of the lactone (III) from the 5Z-carbacyclin compound (II); the step is, accordingly, referred to herein as "the third step".
- the compound of formula (I) or salt or ester thereof is reacted with a compound of formula (VI): ##STR14## (in which R 5 , R 6 and M are as defined above), followed by reaction with a compound of formula (VII):
- R 7 represents an alkyl group having from 1 to 4 carbon atoms or an aralkyl group and Q represents a halogen atom, an alkanesulphonyloxy group or an arylsulphonyloxy group).
- the compound of formula (VI) is preferably prepared in situ by reaction of a compound of formula (VIII): ##STR15## (in which R 5 and R 6 are as defined above and Z represents a halogen atom) with an alkali metal under a nitrogen atmosphere and in the presence of an inert solvent.
- R 5 and R 6 which may be the same or different, each represents a C 1 -C 6 alkyl group, an aralkyl group or an aryl group.
- alkyl groups which may be straight or branched chain groups, include the methyl, ethyl, propyl, butyl and hexyl groups.
- Suitable aralkyl groups include the benzyl and phenethyl groups, whilst examples of suitable aryl groups include the phenyl, pentafluorophenyl, p-tolyl, p-methoxyphenyl, p-chlorophenyl and naphthyl groups.
- the halogen atom represented by Z in the compound of formula (VIII) is preferably a chlorine or bromine atom.
- Preferred compounds of formula (VIII) include chlorodiphenylphosphine, chlorodi-p-tolylphosphine and bromodiphenylphosphine.
- the preferred alkali metal for reaction with the compound of formula (VIII) and consequently for the alkali metal represented by M in the compound of formula (VI) is lithium.
- the molar ratio of alkali metal to compound (VIII) is preferably from 1:1 to 4:1.
- the reaction of the compound of formula (VIII) with the alkali metal takes place in an inert solvent.
- solvent The nature of the solvent is not critical, provided that it does not interfere with the reactor.
- suitable solvents include: hydrocarbons such as hexane, heptane, benzene or toluene; and ethers such as diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether and diglyme; of these, the ethers are preferred.
- the second stage of this third step reaction is the reaction of the resulting compound of formula (VI) with the compound of formula (I) or salt or ester thereof. This is preferably effected in the same inert solvent as was used for the first stage of the reaction [i.e. the reaction of an alkali metal with the compound of formula (VIII)].
- the third stage of the third step reaction comprises reacting the product of the second stage with a compound of formula (VII).
- Preferred compounds of formula (VII) are those in which R 7 represents a methyl group, an ethyl group or a benzyl group and Q represents a bromine atom, an iodine atom, a methanesulphonyloxy group, a benzenesulphonyloxy group or a p-toluenesulphonyloxy group.
- the third stage of the third step reaction is preferably carried out in the same inert solvent, and preferably in the same reaction system, as was used for the first stage.
- the compound of formula (VI) [and, hence, the compound of formula (VIII)] is preferably employed in a large excess relative to the compound of formula (I), for example a molar ratio of compound (VI) [or (VIII)] to compound (I) of from 1:1 to 20:1.
- a large excess of said compound of formula (VII) is preferred, e.g. a molar ratio of compound (VII) to compound (I) of from 1:1 to 20:1.
- Each of the three stages of the third step reaction is preferably effected at a temperature within the range from -20° C. to +100° C., more preferably at about ambient temperature.
- the time required for the reactions will vary, depending upon the reaction temperature, the solvent and the reagents. However, in general, the time required for the first stage is from 1 hour to 5 hours and the time required for each of the second and third stages is generally from 10 minutes to 3 hours.
- the desired product of formula (V): ##STR16## (in which R 1 , R 2 , R 3 , and X are as defined above) or its salts or ester, preferably a compound of formula (Va) or (Vb), may be recovered from the reaction mixture by conventional means.
- one suitable recovery technique comprises; pouring the reaction mixture into water; acidifying the resulting solution; extracting the solution with a water-immiscible organic solvent; drying the organic extract; and distilling the solvent from the extract to give the desired product.
- This product may, if necessary, be further purified by various conventional techniques, including recrystallisation, preparative thin layer chromatography or column chromatography.
- R 1 , R 2 , R 3 , R 4 and X are as defined above.
- the process comprising the sequence of reactions outlined in the above reaction scheme also forms part of the present invention.
- the reaction scheme shows the use of the preferred compounds of the invention and the preparation and use of the preferred isomers of the respective compounds. It will, of course, be appreciated that other compounds of the invention may be used and that other isomers may be prepared and used.
- step (a) of the above reaction scheme the compound of formula (Ib) is treated with an acid or a base in an inert solvent to produce the dihydroxy compound of formula (Xa).
- suitable acids include, for example: mineral acids, such as hydrochloric acid, sulphuric acid, nitric acid and perchloric acid; sulphonic acids, such as methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid or camphorsulphonic acid; and carboxylic acids, such as acetic acid or trifluoroacetic acid. Of these, acetic acid or camphorsulphonic acid are preferred.
- Suitable bases include alkali metal hydroxides such as lithium hydroxide.
- the nature of the solvent employed in the reaction is not critical, provided that it does not interfere with the reaction.
- the solvent is preferably water or a mixture of water with one or more organic solvents, which may be an alcohol (e.g. methanol or ethanol), an ether (e.g. tetrahydrofuran) or a ketone (e.g. acetone).
- the reaction may be effected over a wide range of temperatures, although we generally prefer to carry out the reaction at a temperature between ambient temperature and 100° C.
- the time required for the reaction will vary, depending upon the reaction temperature and the reagents, but is generally within the range from 30 minutes to 10 hours.
- reaction with an acid in an inert solvent may proceed via step (b) to give the hydroxy lactone of formula (XI).
- the acid employed in step (b) may be any one of the acids exemplified for use in step (a), as may the solvent and other reaction conditions.
- the reaction may proceed to give either the compound of formula (Xa) in step (a) or the compound of formula (XI) in step (b).
- step (d) the compound of formula (Xa) is oxidized to give the compound of formula (IXa).
- the reaction involved is a simple cleavage of the carbon-carbon bond of a 1,2-diol and any oxidizing agent which can be used for this reaction in known compounds may be used in the present invention, provided that it does not affect or substantially affect the remainder of the molecule.
- Suitable oxidizing agents include sodium periodate and lead tetraacetate.
- the oxidation reaction is preferably effected in the presence of a solvent, the nature of which is not critical, provided that it does not interfere with the reaction.
- a solvent the nature of which is not critical, provided that it does not interfere with the reaction.
- preferred solvents include: water; ethers, such as tetrahydrofuran; alcohols, such as methanol or ethanol; ketones, such as acetone; fatty acids, such as acetic acid; and mixtures of two or more thereof.
- preferred solvents are aromatic hydrocarbons, such as benzene, toluene or xylene.
- reaction temperature is not particularly critical and accordingly we normally find it convenient to carry out the reaction at about ambient temperature.
- time required for the reaction will generally be within the range from 10 minutes to 2 hours.
- the desired product can be recovered from the reaction mixture by conventional means.
- one suitable recovery procedure comprises: pouring the reaction mixture into water; if necessary, treating it with a reducing agent or acidifying it; extracting the mixture with a water-immiscible organic solvent; drying the organic solvent; and distilling off the solvent to give the desired product.
- This may, if desired, be further purified by such conventional techniques as recrystallisation, preparative thin layer chromatography and column chromatography.
- the individual products from each of the above steps may be isolated and, if necessary, purified prior to treatment in the next step in the reaction sequence. Alternatively, the reaction products may be employed without intermediate isolation or without purification in the next such step.
- first, second and third steps of the processes of the invention can be employed to convert a 5E-carbacyclin compound to the corresponding 5Z-isomer and, indeed, that the reactions have more general applicability, in that they can be used to convert the E or Z isomer of any ⁇ , ⁇ -unsaturated carboxylic acid (or derivative thereof) to the corresponding Z or E isomer.
- This residue was purified by column chromatography through 30 g of silica gel eluted with 200 ml each of a 5%, 10%, 20%, 30% and 40% v/v mixture of ethyl acetate in hexane. 1.36 g of the title compound was obtained from those fractions eluted with 10% and 20% ethyl acetate in hexane.
- Example 1(a) The procedure described in Example 1(a) was repeated, to give 0.45 g of the corresponding iodo-lactone derivative from 0.40 g of 6,9 ⁇ -methylene-11 ⁇ ,15 ⁇ -dihydroxy-17 ⁇ -methyl-20-isopropylideneprost-5(Z),13(E)-dienoic acid. This was then treated by the procedure described in Example 1(b), to give 0.35 g of the title compound.
- Example 1(a) The procedure described in Example 1(a) was repeated, to give 3.0 g of the corresponding iodo-lactone derivative from 2.5 g of 6,9 ⁇ -methylene-11 ⁇ ,15 ⁇ -bis(2-tetrahydropyranyloxy)prost-5(Z),13(E)-dienoic acid. Because the iodo-lactone derivative was unstable, the procedure described in Example 1(b) was immediately carried out, to give 1.7 g of the title compound.
- Example 1(a) and (b) were repeated, to give 0.21 g of the title compound from 0.45 g of 6,9 ⁇ -methylene-11 ⁇ ,15 ⁇ -bis(2-tetrahydropyranyloxy)-20-methoxyprost-5(Z),13(E)-dienoic acid.
- Example 1(a) and (b) The procedures of Example 1(a) and (b) were repeated, to give 0.17 g of the title compound from 0.31 g of 6,9 ⁇ -methylene-11 ⁇ ,15 ⁇ -bis(2-tetrahydropyranyloxy)-16-methylprost-5(Z),13(E)-dien-18-ynoic acid.
- Example 1(a) and (b) The procedures described in Example 1(a) and (b) were repeated, to give 0.34 g of the title compound from 0.54 g of 6,9 ⁇ -methylene-11 ⁇ ,15 ⁇ -bis(2-tetrahydropyranyloxy)-15-cyclopentyl-16,17,18,19,20-pentanorprost-5(Z),13(E)-dienoic acid.
- Example 1(a) and (b) The procedures described in Example 1(a) and (b) were repeated, to give 0.38 g of the title compound in the form of an oil from 0.71 g of 6,9 ⁇ -methylene-11 ⁇ ,15 ⁇ -bis(2-tetrahydropyranyloxy)-16-phenoxy-17,18,19,20-tetranorprost-5(Z),13(E)-dienoic acid.
- Example 10 The procedure described in Example 10 was repeated, to give 0.95 g of the title compound as an oil from 1.7 g of 5,6-epoxy-6,9 ⁇ -methylene-11 ⁇ ,15 ⁇ -bis(2-tetrahydropyranyloxy)prost-13(E)-enoic acid, prepared as described in Example 5.
- lithium 5,6-dihydroxy-6,9 ⁇ -methylene-11 ⁇ ,15 ⁇ -bis-(2-tetrahydropyranyloxy)-20-methoxyprost-13(E)-enoate or lithium 5,6-dihydroxy-6,9 ⁇ -methylene-11 ⁇ ,15 ⁇ -bis-(2-tetrahydropyranyloxy)-16-methylprost-13(E)-en-18-ynoate were obtained from 5,6-epoxy-6,9 ⁇ -methylene-11 ⁇ ,15 ⁇ -bis(2-tetrahydropyranyloxy)-20-methoxyprost-13(E)-enoic acid (prepared as described in Example 6) or 5,6-epoxy-6,9 ⁇ -methylene-11 ⁇ ,15 ⁇ -bis-(2-tetrahydropyranyloxy)-16-methylprost-13(E)-en-18-ynoic acid (prepared as described in Example 7), respectively. Both lithium salts had the same infrared spectra.
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Abstract
Compounds of formula (I): ##STR1## (in which: R1 and R2 are the same or different and each represents hydrogen or a hydroxy-protecting group:
R3 represents an alkyl group having from 1 to 12 carbon atoms which is optionally substituted, an alkenyl group having from 2 to 12 carbon atoms, an alkynyl group having from 2 to 6 carbon atoms or a cycloalkyl group which is optionally substituted; and
X represents an ethylene group, a trans-vinylene group or an ethynylene group) and salts and esters thereof are useful intermediates in the conversion of 5Z-carbacyclin derivatives to their 5E-isomers and in the preparation of certain other carbacyclin compounds.
Description
The present invention relates to a series of new epoxycarbacyclin derivatives, and provides a process for preparing these derivatives from Z-isomers of corresponding carbacyclin compounds and a process for converting these derivatives to the E-isomers of the corresponding carbocyclin compounds. Overall, the two processes of the invention enable the Z-isomer of a carbacyclin compound to be converted to its corresponding E-isomer in good yield.
Carbacyclin compounds are chemically stable and have been developed for various therapeutic uses, including the treatment of thrombosis. The compounds are produced by chemical synthesis and are normally obtained as mixtures of the E- and Z-isomers with respect to the exo double bond of the compound. For example, U.S. Pat. No. 4,322,435 discloses a series of carbacyclin derivatives, many of which have a double bond at the 5-position; during the synthesis of these compounds, the product is usually obtained as a mixture of the 5E- and 5Z-isomers. However, in general, the 5E-isomer is much more active and useful than its corresponding 5Z-isomer, which may have so little activity as to be of no practical use. Since, in the chemical synthesis of carbacyclin derivatives, a substantial proportion of the starting material is converted into the undesired 5Z-isomer (which substantially reduces the yield of 5E-isomer and hence increases the overall cost of the process), it is desirable to convert the unwanted 5Z-isomer to the valuable 5E-isomer.
We have now discovered a process which enables the 5Z-isomer of certain carbacyclin derivatives to be converted to the corresponding 5E-isomer proceding via certain novel epoxycarbacyclin derivatives.
Accordingly, the present invention provides epoxycarbacyclin derivatives of formula (I): ##STR2## (in which: R1 and R2 are the same or different and each represents hydrogen or a hydroxy-protecting group;
R3 represents an alkyl group having from 1 to 12 carbon atoms which is optionally substituted, an alkenyl group having from 2 to 12 carbon atoms, an alkynyl group having from 2 to 6 carbon atoms or a cycloalkyl group which is optionally substituted; and
X represents an ethylene group, a trans-vinylene group or an ethynylene group)
and salts and esters thereof.
The invention also provides a process for preparing compounds of formula (I), as defined above, and their salts and esters, which comprises reacting a 5Z-carbacyclin derivative of formula (II): ##STR3## (in which R1, R2, R3 and X are as defined above) with iodine and with an alkali metal iodide in the presence of a base to give a lactone of formula (III): ##STR4## (in which R1, R2, R3 and X are as defined above) and reacting said lactone of formula (III) with water or an alcohol, to give said compound of formula (I), and, if necessary, salifying or esterifying said compound of formula (I).
The invention further provides a process for preparing a 5E-carbacyclin derivative of formula (V): ##STR5## (in which R1, R2, R3 and X are as defined above) and salts and esters thereof, which comprises reacting an epoxycarbacyclin derivative of formula (I), defined above, or a salt or ester thereof with a phosphorus compound of formula (VI): ##STR6## (in which R5 and R6 are the same or different and each represents an alkyl group having from 1 to 6 carbon atoms, an aralkyl group or an aryl group and M represents an alkali metal atom) and then treating the product with a compound of formula (VII):
R.sup.7 --Q (VII)
(in which R7 represents an alkyl group having from 1 to 4 carbon atoms, or an aralkyl group and Q represents a halogen atom, an alkanesulphonyloxy group or an arylsulphonyloxy group), to give said compound of formula (V) or a salt or ester thereof.
In a preferred embodiment, the invention provides a process for converting a 5Z-carbacyclin derivative of formula (II) to its corresponding 5E-carbacyclin compound of formula (V) by preparing said epoxycarbacyclin derivative of formula (I) or a salt or ester thereof from said 5Z-carbacyclin derivative of formula (II), by the first-mentioned process of the invention and then converting said epoxycarbacyclin derivative of formula (I) or salt or ester thereof to said 5E-carbacyclin derivative of formula (V) or a salt or ester thereof by the second-mentioned process of the invention.
The compounds of the invention can exist in the form of various geometric isomers and other stereoisomers, particularly with respect to the double ring system. Preferred isomers of the compounds of formula (I) are those of formula (Ia): ##STR7## (in which R1, R2, R3 and X are as defined above) and the salts and esters preferably have a corresponding configuration. Accordingly, compounds of formulae (II), (III) and (V) preferably have an equivalent configuration, e.g. compounds of formula (Va): ##STR8## (in which R1, R2, R3 and X are as defined above), the salts and esters preferably having a corresponding configuration.
In the compounds of formulae (I), (II), (III) and (V), R1 and R2 may be the same or different and each represents a hydrogen atom or a hydroxy-protecting group. Although R1 and R2 may be different, we prefer that either both should be hydrogen atoms or both should be hydroxy-protecting groups. Where both R1 and R2 represent hydroxy-protecting groups, these likewise may be the same or different, but it is generally more convenient if the two hydroxy-protecting groups represented by R1 and R2 are the same. In general, prior to any therapeutic use of the compounds, any hydroxy-protecting groups represented by R1 and R2 will be removed from the compound. Accordingly, since these groups are removed, they have no effect on the therapeutic activity of any compounds and they may, accordingly, be chosen solely for their convenience and/or effectiveness as hydroxy-protecting groups. Accordingly, any hydroxy-protecting groups known in the art for use with compounds of this type may equally be employed in the present invention, without any restriction. One preferred class of hydroxy-protecting groups comprises substituted C1 -C4 alkyl groups having a C1 -C4 alkoxy, C1 -C4 alkylthio, trihalomethyl or aralkyloxy substituent at the α-position; specific examples include the methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, benzyloxymethyl, p-nitrobenzyloxymethyl, p-bromobenzyloxymethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 1-methoxyethyl, 1-ethoxyethyl, 1-methoxy-1-methylethyl or 1-ethyl-1-methoxyethyl groups. Where the substituent on the alkyl group is an alkoxy, alkylthio or aralkyloxy group, this substituent may itself be substituted, the substituents being, for example, those suggested as substituents for the alkyl group or they may be alkyl groups. An example of such a substituted group is the 2-methoxyethoxymethyl group. Other preferred substituents on alkyl groups represented by R1 or R2 include aryl groups, i.e. the hydroxy-protecting group represented by R1 or R2 is an aralkyl group; examples of such aralkyl groups include the benzyl, p-nitrobenzyl, p-bromobenzyl, 1-methyl-1-phenylethyl, 1-ethyl-1-phenylethyl, diphenylmethyl and trityl (triphenylmethyl) groups.
Other hydroxy-protecting groups which may be represented by R1 and/or R2 include heterocyclic groups, such as the 4-methoxytetrahydrothiopyran-4-yl group and groups of formula ##STR9## (in which n is an integer of from 3 to 5).
Other preferred hydroxy-protecting groups which may be represented by R1 and/or R2 include trialkylsilyl, dialkylphenylsilyl and diphenylalkylsilyl groups, in which the or each alkyl group has from 1 to 4 carbon atoms. Examples of such groups include the trimethylsilyl, triethylsilyl, dimethylisopropylsilyl, t-butyl-dimethylsilyl, dimethylphenylsilyl and diphenyl-t-butylsilyl groups.
Further preferred hydroxy-protecting groups which may be represented by R1 and/or R2 include acyl groups, especially carboxylic acyl groups and most preferably alkanoyl or arylcarbonyl groups, such as the acetyl, propionyl, butyryl, benzoyl and p-methylbenzoyl groups.
However, it should be emphasized that the above hydroxy-protecting groups are given for exemplification only and that, because of the non-criticality of the groups represented by R1 and R2, any hydroxy-protecting group may be employed in this position, provided that it may be introduced and removed without substantially affecting the remainder of the molecule.
Preferred hydroxy-protecting groups represented by R1 and R2 include: substituted C1 -C4 alkyl groups having one or more C1 -C4 alkoxy, C1 -C4 alkylthio, trihalomethyl or aralkyloxy, substituents at the α-position; the 2-methoxyethoxymethyl group; the tetrahydrofuran-2-yl group; the tetrahydropyran-2-yl group; the 4-methoxytetrahydrothiopyran-4-yl group; a trialkylsilyl or dialkylphenylsilyl group in which each alkyl group has from 1 to 4 carbon atoms; the acetyl group; the propionyl group; or the benzoyl group. Particularly preferred hydroxy-protecting groups which may be represented by R1 and/or R2 are the methoxymethyl, tetrahydropyran-2-yl, t-butyldimethylsilyl, acetyl and benzoyl groups.
R3 represents an optionally substituted C1 -C12 alkyl group, a C2 -C12 alkenyl group, a C2 -C6 alkynyl group or an optionally substituted cycloalkyl group.
Where R3 represents an optionally substituted alkyl group, the alkyl group, which may be a straight or branched chain group, may be, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, 1-methylpentyl, 2-methylpentyl, hexyl, heptyl, 1,1-dimethylpentyl, 1-methylhexyl, 2-methylhexyl, 2-ethylpentyl, octyl, 2-methyloctyl, nonyl, 2-methylnonyl, 2-ethyloctyl, decyl, 2-methyldecyl or 2-ethyldecyl group.
A wide range of substituents is possible on the alkyl group represented by R3, for example halogen atoms, alkoxy groups, optionally substituted cycloalkyl groups, optionally substituted aryl groups and groups of formula --Y--A (in which Y represents an oxygen or sulphur atom or an --NH group and A represents an optionally substituted aryl group). Where R3 represents an unsubstituted alkyl group or a substituted alkyl group having a halogen or alkoxy substituent, the alkyl group is preferably a C4 -C10 alkyl group, for example a butyl, isobutyl, pentyl, isopentyl, 1-methylpentyl, 2-methylpentyl, hexyl, heptyl, 1,1-dimethylpentyl, 1-methylhexyl, 2-methylhexyl, 2-ethylpentyl, octyl, 2-methyloctyl or 2-ethyloctyl group, more preferably a pentyl, 1-methylpentyl, hexyl, 1,1-dimethylpentyl, 1-methylhexyl or 2-methylhexyl group. Where R3 represents a substituted alkyl group having an optionally substituted cycloalkyl, optionally substituted aryl or --Y--A substituent, the alkyl group preferably has from 1 to 3 carbon atoms, i.e. a methyl, ethyl, propyl or isopropyl group, more preferably a methyl or ethyl group.
Where the substituent on the alkyl group represented by R3 is a halogen atom, this is preferably a fluorine, chlorine or bromine atom. Where the substituent on the alkyl group represented by R3 is an alkoxy group, it is preferably a C1 -C4 alkoxy group, which may be a straight or branched chain group, for example a methoxy, ethoxy, propoxy, isopropoxy or butoxy group.
Where R3 represents a cycloalkyl group or a substituted alkyl group having an optionally substituted cycloalkyl substituent, the cycloalkyl group preferably has from 3 to 7 ring carbon atoms and examples include the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups. Examples of substituents on these cycloalkyl groups include: halogen atoms, such as fluorine, chlorine or bromine atoms; alkyl groups having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl and butyl groups; and the trifluoromethyl group; preferred substituents are the methyl and ethyl groups. Where the cycloalkyl group is a substituent on an alkyl group represented by R3, it is preferably a cyclopentyl or cyclohexyl group, which may be unsubstituted or may have one or more substituents as noted above. Where the cycloalkyl group itself is represented by R3, it is preferably a cyclohexyl, cyclopentyl or 1-butylcyclopropyl group.
Where the substituent on the alkyl group represented by R3 is an optionally substituted aryl group or a group of formula --Y--A. A representing an optionally substituted aryl group, the aryl group is preferably a phenyl or naphthyl group, more preferably a phenyl group. This aryl group may be substituted or unsubstituted; where it is substituted, examples of suitable substituents are the same as those given as substituents for cycloalkyl groups in the preceding paragraph. Where the substituent on the alkyl group represented by R3 is a group of formula --Y--A. Y may represent an oxygen atom, a sulphur atom or an --NH group, preferably an oxygen atom or a sulphur atom.
Particularly preferred substituents on the alkyl group represented by R3 include the fluorine atom and methoxy, ethoxy, cyclopentyl, 3-methylcyclopentyl, 3-ethylcyclopentyl, cyclohexyl, 3-methylcyclohexyl, 3-ethylcyclohexyl, phenyl, m-chlorophenyl, phenoxy, phenylthio and p-trifluoromethylphenoxy groups.
Where R3 represents an alkenyl group, it is a group having from 2 to 12 carbon atoms and may be a straight or branched chain group. Examples of such groups include the vinyl, allyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 4-hexenyl, 5-hexenyl, 1,4-dimethyl-3-pentenyl, 5-heptenyl, 6-methyl-5-heptenyl, 2,6-dimethyl-5-heptenyl, 1,1,6-trimethyl-5-heptenyl, 6-methyl-5-octenyl, 2,6-dimethyl-5-octenyl, 6-ethyl-5-octenyl, 2-methyl-6-ethyl-5-octenyl and 2,6-diethyl-5-octenyl groups. We prefer alkenyl groups having from 4 to 12 carbon atoms, for example the 2-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 4-hexenyl, 5-hexenyl, 1,4-dimethyl-3-pentenyl, 5-heptenyl, 6-methyl-5-heptenyl, 2,6-dimethyl-5-heptenyl, 1,1,6-trimethyl-5-heptenyl, 6-methyl-5-octenyl, 2,6-dimethyl-5-octenyl, 6-ethyl-5-octenyl, 2-methyl-6-ethyl-5-octenyl and 2,6-diethyl-5-octenyl groups, more preferably the 2-pentenyl, 4-pentenyl, 4-hexenyl, 5-hexenyl, 6-methyl-5-heptenyl and 2,6-dimethyl-5-heptenyl groups.
Where R3 represents an alkynyl group having from 2 to 6 carbon atoms, it may be a straight or branched chain group; examples include the ethynyl, propargyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 1-methyl-2-pentynyl and 1-methyl-3-pentynyl groups, of which we prefer the alkynyl groups having from 4 to 6 carbon atoms such as the 2-butynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-pentynyl and 1-methyl-3-pentynyl groups, most preferably the 1-methyl-3-pentynyl group.
X, which may represent an ethylene, trans-vinylene or ethynylene group, is preferably an ethylene or trans-vinylene group.
Where the compound of the invention is an ester, it is preferably a C1 -C4 alkyl ester or an aralkyl ester. Particularly preferred compounds of formula (I) are, accordingly, those of formula (Ib), whilst particularly preferred compounds of formula (V) are those of formula (Vb): ##STR10## (in which R1, R2, R3 and X are as defined above and R4 represents a hydrogen atom, a C1 -C4 alkyl group or an aralkyl group).
Examples of C1 -C4 alkyl groups, which may be represented by R4 in the compounds of formulae (Ib) and (Vb) and which may be the ester moiety of esters of compounds of formulae (I) and (V) include straight or branched chain groups, preferably a methyl, ethyl, propyl, isopropyl or butyl group, more preferably a methyl or ethyl group. Examples of aralkyl groups, which may be represented by R4 or may be the aforesaid ester moiety include the benzyl, p-bromobenzyl and p-nitrobenzyl groups, more preferably the benzyl group.
Compounds of formula (I) form salts and these salts, preferably with a pharmaceutically acceptable cation [although, since the compounds of formula (I) are intermediates, this is not essential], also form part of the present invention. Examples of such salts include salts with alkali metals, such as lithium, sodium or potassium, preferably sodium or potassium.
Particularly preferred classes of compound of formula (I), (Ia) and (Ib) are as follows:
(A) Compounds in which:
R1 and R2 are the same or different and each represents a hydrogen atom or a hydroxy-protecting group;
R3 represents a C4 -C10 alkyl group which is unsubstituted or which has one or more fluorine, methoxy or ethoxy substituents; a C1 -C3 alkyl group having one or more cyclopentyl, 3-methylcyclopentyl, 3-ethylcyclopentyl, cyclohexyl, 3-methylcyclohexyl, 3-ethylcyclohexyl, phenyl, p-trifluoromethylphenoxy, phenoxy, phenylthio or p-tolyloxy substituents; a C4 -C12 alkenyl group; a C4 -C6 alkynyl group; a cyclopentyl group; a 3-methylcyclopentyl group; a 3-ethylcyclopentyl group; a cyclohexyl group; a 3-methylcyclohexyl group; or a 3-ethylcyclohexyl group; and
X represents an ethylene, trans-vinylene or ethynylene group;
and salts and aralkyl and C1 -C4 alkyl esters thereof.
(B) Compounds in which:
R3 and X are as defined for class (A) and in which R1 and R2 are the same or different and each represents: a hydrogen atom; a C1 -C4 alkyl group having at its α-position a C1 -C4 alkoxy, C1 -C4 alkylthio, aralkyloxy or trihalomethyl substituent; a 2-methoxyethoxymethyl group; a tetrahydrofuran-2-yl group; a tetrahydropyran-2-yl group; a 4-methoxytetrahydrothiopyran-4-yl group; a trialkylsilyl or dialkylphenylsilyl group, in which each alkyl group has from 1 to 4 carbon atoms; an acetyl group; a propionyl group; or a benzoyl group;
and salts and aralkyl and C1 -C4 alkyl esters thereof.
(C) Compounds in which:
R1 and R2 are the same or different and each represents a hydrogen atom or a methoxymethyl, tetrahydropyran-2-yl, t-butyl-dimethylsilyl, acetyl or benzoyl group;
R3 represents a pentyl, 1-methylpentyl, hexyl, 1-methylhexyl, 1,1-dimethylpentyl, 2-methylhexyl, 2-ethoxy-1,1-dimethylethyl, 5-methoxypentyl, 5-methoxy-1-methylpentyl, 1-fluoropentyl, cyclopentylmethyl, 3-methylcyclopentylmethyl, 2-cyclopentylethyl, 2-cyclopentyl-1-methylethyl, cyclohexylmethyl, 3-ethylcyclohexylmethyl, 2-cyclohexylethyl, benzyl, phenethyl, p-methylbenzyl, phenoxymethyl, m-chlorophenoxymethyl, phenylthiomethyl, 2-pentenyl, 4-pentenyl, 4-hexenyl, 5-hexenyl, 6-methyl-5-heptenyl, 2,6-dimethyl-5-heptenyl, 3-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, cyclopentyl, 3-ethylcyclopentyl, cyclohexyl, 3-methylcyclohexyl or 1-butylcyclopropyl group; and
X represents an ethylene or trans-vinylene group;
and salts and methyl or ethyl esters thereof.
(D) Compounds in which:
R1 and R2 are the same or different and each represents a hydrogen atom, a tetrahydropyran-2-yl group, a t-butyl-dimethylsilyl group or an acetyl group;
R3 represents a pentyl, 1-methylhexyl, 1,1-dimethylpentyl, 5-methoxypentyl, phenoxymethyl, 2-pentenyl, 4-pentenyl, 4-hexenyl, 5-hexenyl, 6-methyl-5-heptenyl, 2,6-dimethyl-5-heptenyl, 1-methyl-3-pentynyl or cyclopentyl group; and
X represents a trans-vinylene group;
and salts and methyl esters thereof.
As is conventional, the compounds of the invention are named as derivatives of prostanoic acid. Thus, the nomenclature is based upon compounds in which R3 represents a C5 group and the numbering system employed is as shown on the following skeletal structure: ##STR11##
Compounds in which R3 represents a group having fewer than 5 carbon atoms are designated by the prefix "nor", "dinor" etc. which denotes the elimination of 1 or 2 etc. methylene groups from the carbon chain in the above skeletal structure, whilst compounds in which R3 represents a group having more than 5 carbon atoms are designated by the prefix "homo", "dihomo" etc, which denotes the insertion of 1 or 2 etc methylene groups into the carbon chain in the above skeletal structure.
Examples of preferred compounds of formula (I) are given in the following list:
1. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-20-norprost-13(E)-enoic acid
2. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)prostanoic acid
3. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)prost-13(E)-enoic acid
4. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydrofuranyloxy)prost-13-ynoic acid
5. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17-methyl-20-norprostanoic acid
6. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-20-methylprost-13(E)-enoic acid
7. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17-methylprostanoic acid
8. 5,6-Epoxy-6,9α-methylene-11α,15α-diacetoxy-18-methylprostanoic acid
9. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-20-ethylprost-13(E)-enoic acid
10. 5,6-Epoxy-6,9α-methylene-11α,15α-diacetoxy-17,20-dimethylprostanoic acid
11. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17,20-dimethylprost-13(E)-enoic acid
12. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(t-butyldimethylsilyloxy)-16,16-dimethylprostanoic acid
13. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16,16-dimethylprost-13(E)-enoic acid
14. 5,6-Epoxy-6,9α-methylene-11α,15α-dibenzoyloxy-16-fluoroprostanoic acid
15. 5,6-Epoxy-6,9α-methylene-11α,15α-bis-(2-tetrahydropyranyloxy)-20-methoxyprostanoic acid
16. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-20-methoxyprost-13(E)-enoic acid
17. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)16-methyl-19-methoxy-20-norprost-13(E)-enoic acid
18. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydrofuranyloxy)-16-methyl-19-methoxy-20-norprost-13-ynoic acid
19. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(methoxymethoxy)-16,16-dimethyl-17-ethoxy-18,19,20-trinorprostanoic acid
20. 5,6-Epoxy-6,9α-methylene-11α,15α-diacetoxy-16,16-dimethyl-17-ethoxy-18,19,20-trinorprost-13(E)-enoic acid
21. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)prost-13(E),19-dienoic acid
22. 5,6-Epoxy-6,9α-methylene-11α,15α-diacetoxyprost-18-enoic acid
23. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)prost-13(E),18-dienoic acid
24. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)prost-17-enoic acid
25. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)prost-13(E),17-dienoic acid
26. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(t-butyldimethylsilyloxy)prost-13-yn-17-enoic acid
27. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-20-methyleneprostanoic acid
28. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-20-methylprost-13(E),19-dienoic acid
29. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(t-butyldimethylsilyloxy)-16,20-dimethylprost-13(E),19-dienoic acid
30. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16,19-dimethylprost-18-enoic acid
31. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-20-isopropylideneprostanoic acid
32. 5,6-Epoxy-6,9α-methylene-11α,15α-diacetoxy-20-isopropylideneprost-13(E)-enoic acid
33. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(t-butyldimethylsilyloxy)-20-isopropylideneprost-13-ynoic acid
34. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16,20,20-trimethylprost-19-enoic acid
35. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(methoxymethoxy)-16,20,20-trimethylprost-13(E),19-dienoic acid
36. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-20-(2-methyl-1-propenyl)prostanoic acid
37. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-20-(2-methyl-1-propenyl)prost-13(E)-enoic acid
38. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-methyl-20-isopropylideneprost-13(E)-enoic acid
39. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17-methyl-20-isopropylideneprostanoic acid
40. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17-methyl-20-isopropylideneprost-13(E)-enoic acid
41. 5,6-Epoxy-6,9α-methylene-11α,15α-diacetoxy-17β-methyl-20-isopropylideneprost-13(E)-enoic acid
42. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(t-butyldimethylsilyloxy)-17-methyl-20-isopropylideneprost-13-ynoic acid
43. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-20-(1-ethylpropylidene)prost-13(E)-enoic acid
44. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17-methyl-20-(1-ethylpropylidene)prost-13(E)-enoic acid
45. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(t-butyldimethylsilyloxy)-16-methylprost-18-ynoic acid
46. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-methyl-20-norprost-13(E)-en-17-ynoic acid
47. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-methylprost-17-ynoic acid
48. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-methylprost-13(E)-en-17-ynoic acid
49. 5,6-Epoxy-6,9α-methylene-11α,15α-dibenzoyloxy-16-methylprost-13(E)-en-17-ynoic acid
50. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-15-cyclopentyl-16,17,18,19,20-pentanorprostanoic acid
51. 5,6-Epoxy-6,9α-methylene-11α,15α-dibenzoyloxy-15-cyclopentyl-16,17,18,19,20-pentanorprostanoic acid
52. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-15-cyclopentyl-16,17,18,19,20-pentanorprost-13(E)-enoic acid
53. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(t-butyl-dimethylsilyloxy)-15-cyclopentyl-16,17,18,19,20-pentanorprost-13(E)-enoic acid
54. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(benzyloxymethoxy)-15-cyclopentyl-16,17,18,19,20-pentanorprost-13-ynoic acid
55. 5,6-Epoxy-6,9α-methylene-11α,15α-dipropionyloxy-15-(3-ethylcyclopentyl)-16,17,18,19,20-pentanorprost-13(E)-enoic acid
56. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-15-cyclohexyl-16,17,18,19,20-pentanorprostanoic acid
57. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-15-cyclohexyl-16,17,18,19,20-pentanorprost-13(E)-enoic acid
58. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16,16-ethyleneprostanoic acid
59. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydrofuranyloxy)-16,16-ethyleneprost-13(E)-enoic acid
60. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16,16-ethyleneprost-13-ynoic acid
61. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-cyclopentyl-17,18,19,20-tetranorprostanoic acid
62. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(t-butyl-dimethylsilyloxy)-16-cyclopentyl-17,18,19,20-tetranorprost-13(E)-enoic acid
63. 5,6-Epoxy-6,9α-methylene-11α,15α-diacetoxy-16-(3-methylcyclopentyl)-17,18,19,20-tetranorprostanoic acid
64. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-(3-ethylcyclopentyl)-17,18,19,20-tetranorprost-13-ynoic acid
65. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(t-butyldimethylsilyloxy)-16-cyclohexyl-17,18,19,20-tetranorprostanoic acid
66. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-cyclohexyl-17,18,19,20-tetranorprost-13(E)-enoic acid
67. 5,6-Epoxy-6,9α-methylene-11α,15α-diacetoxy-17-cyclopentyl-18,19,20-trinorprostanoic acid
68. 5,6-Epoxy-6,9α-methylene-11α,15α-diacetoxy-17-(3-methylcyclopentyl)-18,19,20-trinorprost-13(E)-enoic acid
69. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17-cyclohexyl-18,19,20-trinorprost-13(E)-enoic acid
70. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-methyl-17-cyclopentyl-18,19,20-trinorprostanoic acid
71. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(t-butyl-dimethylsilyloxy)-16-methyl-17-cyclohexyl-18,19,20-trinorprost-13(E)-enoic acid
72. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16,16-dimethyl-17-cyclopentyl-18,19,20-trinorprostanoic acid
73. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydrofuranyloxy)-16,16-dimethyl-18-cyclohexyl-19,20-dinorprost-13(E)-enoic acid
74. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(t-butyl-dimethylsilyloxy)-16-phenyl-17,18,19,20-tetranorprostanoic acid
75. 5,6-Epoxy-6,9α-methylene-11α,15α-diacetoxy-16-phenyl-17,18,19,20-tetranorprost-13(E)-enoic acid
76. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-(m-chlorophenyl)-17,18,19,20-tetranorprostanoic acid
77. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydrofuranyloxy)-17-phenyl-18,19,20-trinorprost-13(E)-enoic acid
78. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17-(m-bromophenyl)-18,19,20-trinorprostanoic acid
79. 5,6-Epoxy-6,9α-methylene-11α,15α-dibenzoyloxy-17-(m-trifluoromethylphenyl)-18,19,20-trinorprost-13(E)-enoic acid
80. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-phenoxy-17,18,19,20-tetranorprostanoic acid
81. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-phenoxy-17,18,19,20-tetranorprost-13(E)-enoic acid
82. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(t-butyl-dimethylsilyloxy)-16-p-tolyloxy-17,18,19,20-tetranorprostanoic acid
83. 5,6-Epoxy-6,9α-methylene-11α,15α-diacetoxy-16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranorprost-13(E)-enoic acid
84. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-(m-chlorophenoxy)-17,18,19,20-tetranorprost-13(E)-enoic acid
85. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydrofuranyloxy)-16-(o-fluorophenoxy)-17,18,19,20-tetranorprostanoic acid
86. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-phenylthio-17,18,19,20-tetranorprostanoic acid
87. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-phenylthio-17,18,19,20-tetranorprost-13(E)-enoic acid
88. 5,6-Epoxy-6,9α-methylene-11α,15α-diacetoxy-16-m-tolylthio-17,18,19,20-tetranorprostanoic acid
89. 5,6-Epoxy-6,9α-methylene-11α,15α-diacetoxy-16-(p-bromophenylthio)-17,18,19,20-tetranorprostanoic acid
90. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-phenylamino-17,18,19,20-tetranorprostanoic acid
91. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydrofuranyloxy)-16-phenylamino-17,18,19,20-tetranorprost-13(E)-enoic acid
92. 5,6-Epoxy-6,9α-methylene-11α-hydroxy-15α-(2-tetrahydropyranyloxy)prostanoic acid
93. 5,6-Epoxy-6,9α-methylene-11α-(2-tetrahydropyranyloxy)-15.alpha.-hydroxyprost-13(E)-enoic acid
94. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxyprostanoic acid
95. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxyprost-13(E)-enoic acid
96. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxyprost-13-ynoic acid
97. 5,6-Epoxy-6,9α-methylene-11α-hydroxy-15α-(2-tetrahydrofuranyloxy)prostanoic acid
98. 5,6-Epoxy-6,9α-methylene-11α-(2-tetrahydrofuranyloxy)-15.alpha.-hydroxyprost-13(E)-enoic acid
99. 5,6-Epoxy-6,9α-methylene-11α-(2-tetrahydropyranyloxy)-15.alpha.-acetoxyprost-13(E)-enoic acid
100. 5,6-Epoxy-6,9α-methylene-11α-hydroxy-15α-acetoxyprost-13(E)-enoic acid
101. 5,6-Epoxy-6,9α-methylene-11α-(t-butyldimethylsilyloxy)-15.alpha.-hydroxyprostanoic acid
102. 5,6-Epoxy-6,9α-methylene-11α-(t-butyldimethylsilyloxy)-15.alpha.-acetoxyprost-13(E)-enoic acid
103. 5,6-Epoxy-6,9α-methylene-11α-(2-tetrahydropyranyloxy)-15.alpha.-(2-tetrahydrofuranyloxy)prostanoic acid
104. 5,6-Epoxy-6,9α-methylene-11α-acetoxy-15α-hydroxyprost-13(E)-enoic acid
105. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-17,20-dimethylprostanoic acid
106. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-17,20-dimethylprost-13(E)-enoic acid
107. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16,16-dimethylprost-13(E)-enoic acid
108. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-20-methoxyprostanoic acid
109. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16,16-dimethyl-17-ethoxy-18,19,20-trinorprost-13(E)-enoic acid
110. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxyprost-17-enoic acid
111. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-20-isopropylideneprostanoic acid
112. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-17β-methyl-20-isopropylideneprost-13(E)-enoic acid
113. 5,6-Epoxy-6,9α-methylene-11α-hydroxy-15α-(2-tetrahydropyranyloxy)-17-methyl-20-isopropylideneprostanoic acid
114. 5,6-Epoxy-6,9α-methylene-11α-(2-tetrahydropyranyloxy)-15.alpha.-hydroxy-17-methyl-20-isopropylideneprost-13(E)-enoic acid
115. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-17-methyl-20-isopropylideneprost-13-ynoic acid
116. 5,6-Epoxy-6,9α-methylene-11α-(2-tetrahydropyranyloxy)-15.alpha.-(2-tetrahydrofuranyloxy)-17-methyl-20-isopropylideneprost-13(E)-enoic acid
117. 5,6-Epoxy-6,9α-methylene-11α-acetoxy-15α-benzoyloxy-17-methyl-20-isopropylideneprostanoic acid
118. 5,6-Epoxy-6,9α-methylene-11α-hydroxy-15α-acetoxy-17-methyl-20-isopropylideneprostanoic acid
119. 5,6-Epoxy-6,9α-methylene-11α-hydroxy-15α-acetoxy-17-methyl-20-isopropylideneprost-13(E)-enoic acid
120. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-methylprost-18-ynoic acid
121. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-methylprost-13(E)-en-18-ynoic acid
122. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-methylprost-13,18-diynoic acid
123. 5,6-Epoxy-6,9α-methylene-11α-hydroxy-15α-(2-tetrahydropyranyloxy)-16-methylprost-13(E)-en-18-ynoic acid
124. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-methylprost-17-ynoic acid
125. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-methylprost-13(E)-en-17-ynoic acid
126. 5,6-Epoxy-6,9α-methylene-11α-acetoxy-15α-hydroxy-16-methylprost-17-ynoic acid
127. 5,6-Epoxy-6,9α-methylene-11α-benzoyloxy-15α-hydroxy-16-methylprost-13(E)-en-17-ynoic acid
128. 5,6-Epoxy-6,9α-methylene-11α-hydroxy-15α-(2-tetrahydropyranyloxy)-15-cyclopentyl-16,17,18,19,20-pentanorprostanoic acid
129. 5,6-Epoxy-6,9α-methylene-11α-hydroxy-15α-(2-tetrahydropyranyloxy)-15-cyclopentyl-16,17,18,19,20-pentanorprost-13(E)-enoic acid
130. 5,6-Epoxy-6,9α-methylene-11α-(2-tetrahydropyranyloxy)-15.alpha.-hydroxy-15-cyclopentyl-16,17,18,19,20-pentanorprostanoic acid
131. 5,6-Epoxy-6,9α-methylene-11α-(2-tetrahydropyranyloxy)-15.alpha.-hydroxy-15-cyclopentyl-16,17,18,19,20-pentanorprost-13(E)-enoic acid
132. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-15-cyclopentyl-16,17,18,19,20-pentanorprostanoic acid
133. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-15-cyclopentyl-16,17,18,19,20-pentanorprost-13(E)-enoic acid
134. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-15-cyclopentyl-16,17,18,19,20-pentanorprost-13-ynoic acid
135. 5,6-Epoxy-6,9α-methylene-11α-(2-tetrahydropyranyloxy)-15.alpha.-hydroxy-15-cyclopentyl-16,17,18,19,20-pentanorprost-13(E)-enoic acid
136. 5,6-Epoxy-6,9α-methylene-11α-hydroxy-15α-(2-tetrahydrofuranyloxy)-15-cyclopentyl-16,17,18,19,20-pentanorprost-13(E)-enoic acid
137. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-15-(3-methylcyclopentyl)-16,17,18,19,20-pentanorprostanoic acid
138. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-15-(3-methylcyclopentyl)-16,17,18,19,20-pentanorprost-13(E)-enoic acid
139. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-15-cyclohexyl-16,17,18,19,20-pentanorprostanoic acid
140. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-15-(3-ethylcyclohexyl)-16,17,18,19,20-pentanorprost-13(E)-enoic acid
141. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16,16-ethyleneprost-13(E)-enoic acid
142. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-cyclopentyl-17,18,19,20-tetranorprost-13(E)-enoic acid
143. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-(3-methylcyclopentyl)-17,18,19,20-tetranorprostanoic acid
144. 5,6-Epoxy-6,9α-methylene-11α,15α-dihyroxy-16-cyclohexyl-17,18,19,20-tetranorprost-13(E)-enoic acid
145. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-cyclohexyl-17,18,19,20-tetranorprostanoic acid
146. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16,16-dimethyl-18-cyclohexyl-19,20-dinorprost-13(E)-enoic acid
147. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-phenyl-17,18,19,20-tetranorprostanoic acid
148. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-phenyl-17,18,19,20-tetranorprost-13(E)-enoic acid
149. 5,6-Epoxy-6,9α-methylene-11α-hydroxy-15α-(2-tetrahydropyranyloxy)-16-p-tolyl-17,18,19,20-tetranorprost-13(E)-enoic acid
150. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-p-tolyl-17,18,19,20-tetranorprost-13(E)-enoic acid
151. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-17-(p-chlorophenyl)-18,19,20-trinorprostanoic acid
152. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-cyclopentylamino-17,18,19,20-tetranorprost-13(E)-enoic acid
153. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-phenoxy-17,18,19,20-tetranorprostanoic acid
154. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-phenoxy-17,18,19,20-tetranorprost-13(E)-enoic acid
155. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-p-tolyloxy-17,18,19,20-tetranorprost-13(E)-enoic acid
156. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-(p-chlorophenoxy)-17,18,19,20-tetranorprost-13(E)-enoic acid
157. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-phenylthio-17,18,19,20-tetranorprostanoic acid
158. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-phenylthio-17,18,19,20-tetranorprost-13(E)-enoic acid
159. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-(p-bromophenylthio)-17,18,19,20-tetranorprostanoic acid
160. 5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-phenylamino-17,18,19,20-tetranorprost-13(E)-enoic acid
161. 5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-methylprost-13(E)-en-18-ynoic acid
162. 5,6-Epoxy-6,9α-methylene-11α,15β-dihydroxyprost-13(E)-enoic acid
163. 5,6-Epoxy-6,9α-methylene-11α,15β-dihydroxyprost-13-ynoic acid
164. 5,6-Epoxy-6,9α-methylene-11α,15β-dihydroxy-17β-methyl-20-isopropylideneprost-13(E)-enoic acid
165. 5,6-Epoxy-6,9α-methylene-11α,15β-dihydroxy-16-methylprost-13(E)-en-18-ynoic acid
166. 5,6-Epoxy-6,9α-methylene-11α,15β-dihydroxy-15-cyclopentyl-16,17,18,19,20-pentanorprost-13(E)-enoic acid
The compounds listed above are the free acids, i.e. compounds of formula (I). In addition, we prefer the methyl, ethyl and benzyl esters and the sodium and potassium salts of the compounds listed above. Of the compounds listed above, particularly preferred compounds are Compounds No. 3, 4, 6, 23, 40, 41, 52, 53, 95, 96, 107, 112, 114, 116, 121, 123, 133, 135 and 161 of which Compounds No. 3, 4, 40, 52 and 161 are most preferred.
The compounds of formula (I) and salts and esters thereof may be prepared by what is effectively a 2-step process, in the first step of which the compound of formula (II): ##STR12## (in which R1, R2, R3 and X are as defined above) is converted to a lactone of formula (III): ##STR13## (in which R1, R2, R3 and X are as defined above) and in the second step of which this lactone is converted to the desired compound of formula (I) or, depending upon reaction conditions and reagents, to a salt or ester thereof. If desired, these steps may be followed by salification or esterification.
In the first step, the 5Z-carbacyclin compound of formula (II) is reacted with iodine and an alkali metal iodide in the presence of a base and preferably in a solvent.
The starting material, the compound of formula (II), may be prepared, for example, by the processes described in British patent specification No. 2,012,265. British patent specification No. 2,017,699, Japanese patent application Kokai (i.e. as laid open to public inspection) No. 55/28945 or European patent application No. 11591.
The molar ratio of iodine to compound of formula (II) is preferably from 1:1 to 2:1.
Where a solvent is employed, its nature is not critical, provided that it does not adversely affect the reaction. Suitable solvents include: water; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, benzyl alcohol or p-nitrobenzyl alcohol; ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or diglyme; amides such as dimethylformamide or dimethylacetamide; sulphoxides such as dimethyl sulphoxide; and mixtures of any two or more thereof. Of these, alcohols are preferred.
Examples of suitable bases include: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide or barium hydroxide; alkali metal carbonates such as sodium carbonate or potassium carbonate; alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide or potassium t-butoxide. Of these, we prefer to use alkali metal carbonates or alkali metal bicarbonates. The molar ratio of base to compound of formula (II) is preferably from 1:1 to 4:1.
Examples of suitable alkali metal iodides include lithium iodide, sodium iodide and potassium iodide, of which potassium iodide is preferred. A large excess of the iodide is preferably employed, for example a molar ratio of iodide to compound of formula (II) of from 1:1 to 10:1.
The reaction temperature is not critical and, accordingly, for convenience the reaction is preferably carried out at ambient temperature. At such a temperature, the time required for the reaction will, depending upon the reactants and other reaction conditions, generally be within the range from 2 hours to 15 hours.
The second step of this reaction sequence comprises reacting the lactone of formula (III) with water or an alcohol, preferably with a compound of formula (IV):
R.sup.4 OH (IV)
(in which R4 is as defined above) in the presence of a base and optionally of a solvent. Examples of suitable bases include those described in relation to the first step; where R4 represents a hydrogen atom, the base is most preferably an alkali metal hydroxide or an alkali metal carbonate; when R4 represents an alkyl group or an aralkyl group, the base is most preferably an alkali metal carbonate or an alkali metal alkoxide.
We prefer to employ a molar ratio of said base to said compound of formula (III) of from 1:1 to 2:1 and a molar ratio of said compound of formula (IV) or other alcohol to said compound of formula (III) of from 1:1 to 2:1.
Examples of suitable solvents include those already given for the first step. However, in this step, the compound of formula (IV) or other alcohol may serve as or as part of the solvent. Specifically, where R4 represents a hydrogen atom, the compound of formula (IV) is water and, accordingly, the solvent employed for this step may be water or a mixture of water with the solvent employed for the first step. Where R4 represents an alkyl or aralkyl group, the compound of formula (IV) is an alcohol and, accordingly, if an excess of this alcohol is employed, then the alcohol itself may serve as the solvent.
The temperature at which the reaction of the second step is carried out is not particularly critical and, accordingly, for convenience we prefer to carry out the reaction at about ambient temperature. At such a temperature, depending upon the reagents and other reaction conditions, the time required for the reaction will generally be within the range from 1 hour to 5 hours.
Where a compound of formula (I) itself has been prepared by the above sequence of reactions, this may, if desired, be converted to the corresponding compound in which R4 represents an alkyl group or an aralkyl group by conventional esterification methods, for example by reacting the compound of formula (I) with a diazoalkane, or by converting said compound of formula (I) to its corresponding acid halide and then treating this acid halide with an alcohol of formula R4 OH. Correspondingly, where an alkyl or aralkyl ester of a compound of formula (I) has been prepared, this may be converted to the corresponding compound where R1 represents a hydrogen atom by conventional deesterification techniques, although this is, in general, less preferred.
Similarly, the compounds may be salified, if necessary, to prepare any desired salt.
After completion of the reaction, the desired product may be recovered from the reaction mixture by conventional means. For example, one suitable recovery technique comprises: pouring the reaction mixture into water; if necessary, treating the resulting mixture with a reducing agent or acidifying it with dilute hydrochloric acid; extracting the mixture with a water-immiscible organic solvent; drying the organic extract; and finally distilling the solvent from the extract to give the desired product. This product may, if necessary, be further purified by such conventional techniques as recrystallisation, preparative thin layer chromatography or column chromatography.
If desired, the intermediate lactone compound of formula (III) obtained in the course of the above reaction sequence may be isolated and purified from the reaction mixture obtained in the first step; however, in general, it is more convenient to carry out the two steps of the above reaction sequence without intermediate isolation of the compound of formula (III).
Compounds of formula (I) can be converted to 5E-carbacyclin derivatives having potent pharmaceutical activity. This step is preferably carried out as a third step in the reaction sequence which starts with the preparation of the lactone (III) from the 5Z-carbacyclin compound (II); the step is, accordingly, referred to herein as "the third step". In this third step, the compound of formula (I) or salt or ester thereof is reacted with a compound of formula (VI): ##STR14## (in which R5, R6 and M are as defined above), followed by reaction with a compound of formula (VII):
R.sup.7 --Q (VII)
(in which R7 represents an alkyl group having from 1 to 4 carbon atoms or an aralkyl group and Q represents a halogen atom, an alkanesulphonyloxy group or an arylsulphonyloxy group).
The compound of formula (VI) is preferably prepared in situ by reaction of a compound of formula (VIII): ##STR15## (in which R5 and R6 are as defined above and Z represents a halogen atom) with an alkali metal under a nitrogen atmosphere and in the presence of an inert solvent.
In the compound of formula (VIII), and consequently in the compound of formula (VI), R5 and R6, which may be the same or different, each represents a C1 -C6 alkyl group, an aralkyl group or an aryl group. Examples of the alkyl groups, which may be straight or branched chain groups, include the methyl, ethyl, propyl, butyl and hexyl groups. Suitable aralkyl groups include the benzyl and phenethyl groups, whilst examples of suitable aryl groups include the phenyl, pentafluorophenyl, p-tolyl, p-methoxyphenyl, p-chlorophenyl and naphthyl groups. The halogen atom represented by Z in the compound of formula (VIII) is preferably a chlorine or bromine atom.
Preferred compounds of formula (VIII) include chlorodiphenylphosphine, chlorodi-p-tolylphosphine and bromodiphenylphosphine.
The preferred alkali metal for reaction with the compound of formula (VIII) and consequently for the alkali metal represented by M in the compound of formula (VI) is lithium. The molar ratio of alkali metal to compound (VIII) is preferably from 1:1 to 4:1.
The reaction of the compound of formula (VIII) with the alkali metal takes place in an inert solvent. The nature of the solvent is not critical, provided that it does not interfere with the reactor. Examples of suitable solvents include: hydrocarbons such as hexane, heptane, benzene or toluene; and ethers such as diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether and diglyme; of these, the ethers are preferred.
The second stage of this third step reaction is the reaction of the resulting compound of formula (VI) with the compound of formula (I) or salt or ester thereof. This is preferably effected in the same inert solvent as was used for the first stage of the reaction [i.e. the reaction of an alkali metal with the compound of formula (VIII)]. The third stage of the third step reaction comprises reacting the product of the second stage with a compound of formula (VII). Preferred compounds of formula (VII) are those in which R7 represents a methyl group, an ethyl group or a benzyl group and Q represents a bromine atom, an iodine atom, a methanesulphonyloxy group, a benzenesulphonyloxy group or a p-toluenesulphonyloxy group. Like the second stage, the third stage of the third step reaction is preferably carried out in the same inert solvent, and preferably in the same reaction system, as was used for the first stage.
The compound of formula (VI) [and, hence, the compound of formula (VIII)] is preferably employed in a large excess relative to the compound of formula (I), for example a molar ratio of compound (VI) [or (VIII)] to compound (I) of from 1:1 to 20:1. Similarly, a large excess of said compound of formula (VII) is preferred, e.g. a molar ratio of compound (VII) to compound (I) of from 1:1 to 20:1.
Each of the three stages of the third step reaction is preferably effected at a temperature within the range from -20° C. to +100° C., more preferably at about ambient temperature. The time required for the reactions will vary, depending upon the reaction temperature, the solvent and the reagents. However, in general, the time required for the first stage is from 1 hour to 5 hours and the time required for each of the second and third stages is generally from 10 minutes to 3 hours.
After completion of the last of these reactions, the desired product of formula (V): ##STR16## (in which R1, R2, R3, and X are as defined above) or its salts or ester, preferably a compound of formula (Va) or (Vb), may be recovered from the reaction mixture by conventional means. For example, one suitable recovery technique comprises; pouring the reaction mixture into water; acidifying the resulting solution; extracting the solution with a water-immiscible organic solvent; drying the organic extract; and distilling the solvent from the extract to give the desired product. This product may, if necessary, be further purified by various conventional techniques, including recrystallisation, preparative thin layer chromatography or column chromatography.
Compounds of formula (I) can also be converted to a compound of formula (IX): ##STR17## preferably a compound of formula (IXa): ##STR18## (in which R1, R2, R3 and X are as defined above). This may be effected by the reactions outlined in the following reaction scheme: ##STR19##
In the above formulae, R1, R2, R3, R4 and X are as defined above. The process comprising the sequence of reactions outlined in the above reaction scheme also forms part of the present invention. The reaction scheme shows the use of the preferred compounds of the invention and the preparation and use of the preferred isomers of the respective compounds. It will, of course, be appreciated that other compounds of the invention may be used and that other isomers may be prepared and used.
In step (a) of the above reaction scheme, the compound of formula (Ib) is treated with an acid or a base in an inert solvent to produce the dihydroxy compound of formula (Xa).
There is no particular limitation upon the nature of the acid used in this reaction and examples of suitable acids include, for example: mineral acids, such as hydrochloric acid, sulphuric acid, nitric acid and perchloric acid; sulphonic acids, such as methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid or camphorsulphonic acid; and carboxylic acids, such as acetic acid or trifluoroacetic acid. Of these, acetic acid or camphorsulphonic acid are preferred. There is equally no particular limitation on the nature of the base used in this reaction, provided that it does not affect other parts of the molecule. Suitable bases include alkali metal hydroxides such as lithium hydroxide.
The nature of the solvent employed in the reaction is not critical, provided that it does not interfere with the reaction. The solvent is preferably water or a mixture of water with one or more organic solvents, which may be an alcohol (e.g. methanol or ethanol), an ether (e.g. tetrahydrofuran) or a ketone (e.g. acetone).
The reaction may be effected over a wide range of temperatures, although we generally prefer to carry out the reaction at a temperature between ambient temperature and 100° C. The time required for the reaction will vary, depending upon the reaction temperature and the reagents, but is generally within the range from 30 minutes to 10 hours.
Alternatively, where R4 in the compound of formula (Ib) represents a hydrogen atom, reaction with an acid in an inert solvent may proceed via step (b) to give the hydroxy lactone of formula (XI). The acid employed in step (b) may be any one of the acids exemplified for use in step (a), as may the solvent and other reaction conditions. Depending upon the precise reaction conditions and the reagents, the reaction may proceed to give either the compound of formula (Xa) in step (a) or the compound of formula (XI) in step (b). Where the compound of formula (XI) is prepared, this may be converted to the compound of formula (Xa) by treatment with a base in an inert solvent, the bases, solvents and reaction conditions being as described for the second step of the processes of the invention, that is to say the conversion of the iodo lactone of formula (III) to the compound of formula (I).
Finally, in step (d) the compound of formula (Xa) is oxidized to give the compound of formula (IXa). The reaction involved is a simple cleavage of the carbon-carbon bond of a 1,2-diol and any oxidizing agent which can be used for this reaction in known compounds may be used in the present invention, provided that it does not affect or substantially affect the remainder of the molecule. Suitable oxidizing agents include sodium periodate and lead tetraacetate.
The oxidation reaction is preferably effected in the presence of a solvent, the nature of which is not critical, provided that it does not interfere with the reaction. Where the oxidizing agent is sodium periodate or a similar compound, preferred solvents include: water; ethers, such as tetrahydrofuran; alcohols, such as methanol or ethanol; ketones, such as acetone; fatty acids, such as acetic acid; and mixtures of two or more thereof. When lead tetraacetate or a similar compound is used as the oxidizing agent, preferred solvents are aromatic hydrocarbons, such as benzene, toluene or xylene.
The reaction temperature is not particularly critical and accordingly we normally find it convenient to carry out the reaction at about ambient temperature. Depending upon the reaction temperature and the reagents, the time required for the reaction will generally be within the range from 10 minutes to 2 hours.
After completion of each of these reaction steps, the desired product can be recovered from the reaction mixture by conventional means. For example, one suitable recovery procedure comprises: pouring the reaction mixture into water; if necessary, treating it with a reducing agent or acidifying it; extracting the mixture with a water-immiscible organic solvent; drying the organic solvent; and distilling off the solvent to give the desired product. This may, if desired, be further purified by such conventional techniques as recrystallisation, preparative thin layer chromatography and column chromatography. If desired, the individual products from each of the above steps, may be isolated and, if necessary, purified prior to treatment in the next step in the reaction sequence. Alternatively, the reaction products may be employed without intermediate isolation or without purification in the next such step.
It is of interest to note that the first, second and third steps of the processes of the invention can be employed to convert a 5E-carbacyclin compound to the corresponding 5Z-isomer and, indeed, that the reactions have more general applicability, in that they can be used to convert the E or Z isomer of any δ,ε-unsaturated carboxylic acid (or derivative thereof) to the corresponding Z or E isomer.
The invention is further illustrated by the following Examples and Preparations.
29 ml of a 0.5N aqueous solution of sodium bicarbonate were added to a solution of 4.0 g of 6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17.beta.-methyl-20-isopropylideneprost-5(Z),13(E)-dienoic acid in 32 ml of isopropanol. The mixture was stirred for 10 minutes, and then a solution of 3.54 g of iodine and 6.96 g of potassium iodide in 20 ml of water was added. The mixture was stirred for 6.5 hours at room temperature and then diluted with a 5% w/v aqueous solution of sodium thiosulphate. The mixture was then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulphate. The solvent was distilled off under reduced pressure, giving 4.91 g of the title compound as an oil.
Infrared Absorption Spectrum (liquid film)νmax cm-1 : 1730.
Nuclear Magnetic Resonance Spectrum (CDCl3)δppm: 4.64 (2H, multiplet); 5.05 (1H, triplet); 5.50 (2H, multiplet).
10 ml of a 10% w/v aqueous solution of sodium hydroxide were added to a solution of 4.9 g of 5-hydroxy-6-iodo-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17β-methyl-20-isopropylideneprost-13(E)-enoic acid 1,5-lactone [prepared as described in step (a) above] in 30 ml of methanol, and the mixture was stirred for 3 hours at room temperature. The mixture was then diluted with ice-water and acidified with dilute hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulphate. The solvent was then distilled off under reduced pressure, giving 4.5 g of an oily residue. This residue was purified by column chromatography through 50 g of silica gel eluted with 200 ml each of a 20%, 30%, 40%, 50% and 60% v/v mixture of ethyl acetate in hexane. 2.6 g of the title compound were obtained with the fractions eluted with 40-60% ethyl acetate in hexane.
Infrared Absorption Spectrum (liquid film)νmax cm-1 : 975, 1710, 1735, 3150.
Nuclear Magnetic Resonance Spectrum (CDCl3)δppm: 4.65 (2H, multiplet); 5.04 (1H, triplet); 5.5 (2H, multiplet); 9.0 (1H, multiplet).
0.50 g of anhydrous potassium carbonate was added to a solution of 2.30 g of 5-hydroxy-6-iodo-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17β-methyl-20-isopropylideneprost-13(E)-enoic acid 1,5-lactone [prepared as described in Example 1(a)] in 23 ml of methanol, and the mixture was stirred for 30 minutes at 60° C. The mixture was then diluted with ice-water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulphate, after which the solvent was distilled off under reduced pressure to give 2.04 g of an oily residue. This residue was purified by column chromatography through 30 g of silica gel eluted with 200 ml each of a 5%, 10%, 20%, 30% and 40% v/v mixture of ethyl acetate in hexane. 1.36 g of the title compound was obtained from those fractions eluted with 10% and 20% ethyl acetate in hexane.
Infrared Absorption Spectrum (liquid film)νmax cm-1 : 1020, 1030, 1740.
Nuclear Magnetic Resonance Spectrum (CDCl3)δppm: 0.9 (3H, multiplet); 3.75 (3H, singlet); 4.75 (2H, multiplet); 4.9-5.9 (3H, multiplet).
A portion of this methyl ester was dissolved in a 80:20 by volume mixture of methanol and water and hydrolyzed with lithium hydroxide. The mixture was then evaporated to dryness, giving the lithium salt of the corresponding carboxylic acid in quantitative yield.
The procedures described in Examples 1(a) and 2 were repeated, to give 0.88 g of the title compound from 1.46 g of 6,9α-methylene-11α,15α-diacetoxy-17β-methyl-20-isopropylideneprost-5(Z),13(E)-dienoic acid.
Infrared Absorption Spectrum (liquid film)νmax cm-1 : 1240, 1735.
Nuclear Magnetic Resonance Spectrum (CDCl3)δppm: 0.88 (3H, doublet); 2.03 (6H, multiplet); 3.65 (3H, singlet).
The procedure described in Example 1(a) was repeated, to give 0.45 g of the corresponding iodo-lactone derivative from 0.40 g of 6,9α-methylene-11α,15α-dihydroxy-17β-methyl-20-isopropylideneprost-5(Z),13(E)-dienoic acid. This was then treated by the procedure described in Example 1(b), to give 0.35 g of the title compound.
Infrared Absorption Spectrum (liquid film)νmax cm-1 : 1740, 3400.
The procedure described in Example 1(a) was repeated, to give 3.0 g of the corresponding iodo-lactone derivative from 2.5 g of 6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)prost-5(Z),13(E)-dienoic acid. Because the iodo-lactone derivative was unstable, the procedure described in Example 1(b) was immediately carried out, to give 1.7 g of the title compound.
Infrared Absorption Spectrum (liquid film)νmax cm-1 : 975, 1710, 1735, 3150.
The procedures of Example 1(a) and (b) were repeated, to give 0.21 g of the title compound from 0.45 g of 6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-20-methoxyprost-5(Z),13(E)-dienoic acid.
Infrared Absorption Spectrum (liquid film)νmax cm-1 : 970, 1710, 1735, 3150.
The procedures of Example 1(a) and (b) were repeated, to give 0.17 g of the title compound from 0.31 g of 6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-methylprost-5(Z),13(E)-dien-18-ynoic acid.
Infrared Absorption Spectrum (liquid film)νmax cm-1 : 975, 1710, 1735, 3150.
The procedures described in Example 1(a) and (b) were repeated, to give 0.34 g of the title compound from 0.54 g of 6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-15-cyclopentyl-16,17,18,19,20-pentanorprost-5(Z),13(E)-dienoic acid.
Infrared Absorption Spectrum (liquid film)νmax cm-1 : 974, 1710, 1740, 3140.
The procedures described in Example 1(a) and (b) were repeated, to give 0.38 g of the title compound in the form of an oil from 0.71 g of 6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-phenoxy-17,18,19,20-tetranorprost-5(Z),13(E)-dienoic acid.
Infrared Absorption Spectrum (liquid film)νmax cm-1 : 970, 1710, 1735.
5 g of chlorodiphenylphosphine were added, with stirring under a stream of nitrogen, to 25 ml of anhydrous tetrahydrofuran containing 0.5 g of metallic lithium. The mixture was stirred for 2 hours at room temperature to prepare a lithium diphenylphosphide solution. 0.6 g of 5,6-epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17β-methyl-20-isopropylideneprost-13(E)-enoic acid [as prepared in Example 1(b)] was dissolved in 6 ml of this lithium diphenylphosphide solution and then the mixture was stirred for 30 minutes under a stream of nitrogen. 1 ml of methyl iodide was then added and the mixture was stirred for a further 30 minutes at room temperature, after which it was diluted with ice-water, acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulphate. The solvent was then distilled off under reduced pressure, giving 1.4 g of a residue. This residue was purified by column chromatography through 28 g of silica gel, eluted with 200 ml each of a 10%, 15%, 20%, 25%, 30% and 35% v/v mixture of ethyl acetate in hexane. 0.4 g of the title compound was obtained from those fractions eluted with 20-30% v/v mixtures of ethyl acetate in hexane.
[α]26 +13.6° (c=1.0, chloroform, sodium D line).
Infrared Absorption Spectrum (liquid film)νmax cm-1 : 975, 1710, 1740, 3100.
Nuclear Magnetic Resonance Spectrum (CDCl3)δppm: 0.9 (3H, multiplet); 4.7 (2H, multiplet); 5.1-5.6 (4H, multiplet).
Following the same procedure, the corresponding methyl ester was treated with a 5 molar excess of lithium diphenylphosphide and the product was treated with methanol, to give the methyl ester of the title compound.
The procedure described in Example 10 was repeated, to give 0.95 g of the title compound as an oil from 1.7 g of 5,6-epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)prost-13(E)-enoic acid, prepared as described in Example 5.
Infrared Absorption Spectrum (liquid film)νmax cm-1 : 1020, 1130, 1710, 1740, 3100.
Nuclear Magnetic Resonance Spectrum (CDCl3)δppm: 4.70 (2H, multiplet); 5.0-5.6 (3H, multiplet).
The procedures described in Examples 1(a) and (b) and 10 were followed in turn, to give 0.8 g of the title compound as an oil from 2.0 g of 6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-15-cyclopentyl-16,17,18,19,20-pentanorprost-5(Z),13(E)-dienoic acid.
Infrared Absorption Spectrum (liquid film)νmax cm-1 : 970, 1710, 1740, 3100.
15 Nuclear Magnetic Resonance Spectrum (CDCl3)δppm: 4.71 (2H, multiplet); 5.1-5.7 (3H, multiplet).
The procedures described in Examples 1(a) and (b) and 10 were repeated in turn, to give 0.58 g of the title compound in the form of an oil from 1.47 g of 6.9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)prost-5(Z),13(E),17(Z)-trienoic acid.
Infrared Absorption Spectrum (liquid film) νmax cm-1 : 978, 1023, 1035, 1710, 1740, 3100.
Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 4.65 (2H, multiplet); 5.0-5.7 (5H, multiplet).
The procedures described in Examples 1(a) and (b) and 10 were repeated in turn, to give 0.79 g of the title compound as an oil from 2.01 g of 6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-20-methyleneprost-5(Z),13(E)-dienoic acid.
Infrared Absorption Spectrum (liquid film) νmax cm-1 : 970, 1020, 1710, 3100.
Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 4.5-6.1 (8H, multiplet).
The procedures described in Examples 1(a) and (b) and 10 were repeated in turn, to give 0.82 g of the title compound in the form of an oil from 2.07 g of 6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-20-methoxyprost-5(Z),13(E)-dienoic acid.
Infrared Absorption Spectrum (liquid film) νmax cm-1 : 970, 1710, 1735, 3100.
Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 4.71 (2H, multiplet); 3.21 (3H, singlet); 5.1-5.6 (3H, multiplet).
The procedures described in Examples 1(a) and (b) and 10 were repeated in turn, to give 0.81 g of the title compound in the form of an oil from 1.97 g of 6.9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16,16-dimethylprost-5(Z),13(E)-dienoic acid.
Infrared Absorption Spectrum (liquid film) νmax cm-1 : 970, 1710, 1735, 3100.
Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 0.7-1.1 (9H, multiplet); 4.70 (2H, multiplet); 5.1-6.0 (3H, multiplet).
The procedures described in Examples 1(a) and (b) and 10 were repeated in turn, to give 0.91 g of the title compound in the form of an oil from 2.3 g of 6.9α-methylene-11α,15β-bis(2-tetrahydropyranyloxy)-prost-5(Z),13(E)-dienoic acid.
Infrared Absorption Spectrum (liquid film) νmax cm-1 : 1710, 1740, 3100.
Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 0.7-1.1 (3H, multiplet); 4.70 (2H, multiplet); 5.0-5.6 (3H, multiplet).
The procedures described in Examples 1(a) and (b) and 10 were repeated in turn, to give 0.39 g of the title compound in the form of an oil from 1.0 g of 6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-20-isopropylideneprost-5(Z),13(E)-dienoic acid.
Infrared Absorption Spectrum (liquid film) νmax cm-1 : 975, 1020, 1710, 1740, 3100.
Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 4.70 (2H, multiplet); 5.1-5.9 (4H, multiplet).
The procedures described in Examples 1(a) and (b) and 10 were repeated in turn, to give 0.60 g of the title compound in the form of an oil from 1.50 g of 6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-phenoxy-17,18,19,20-tetranorprost-5(Z),13(E)-dienoic acid.
Infrared Absorption Spectrum (liquid film) νmax cm-1 : 970, 1030, 3100.
Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 6.80-7.50 (5H, multiplet).
The procedures described in Examples 1(a) and (b) and 10 were repeated in turn, to give 0.85 g of the title compound in the form of an oil from 2.05 g of 6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16,20-dimethylprost-5(Z),13(E)-dienoic acid.
Infrared Absorption Spectrum (liquid film) νmax cm-1 : 970, 1710, 1740, 3100.
Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 0.7-1.1 (6H, multiplet); 4.70 (2H, multiplet); 5.0-5.7 (3H, multiplet).
The procedures described in Examples 1(a) and (b) and 10 were repeated in turn, to give 0.8 g of the title compound in the form of an oil from 1.96 g of 6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-methylprost-5(Z),13(E)-dien-18-ynoic acid
Infrared Absorption Spectrum (liquid film) νmax cm-1 : 970, 1710, 1735, 2960, 3100.
Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 0.9 (3H, multiplet); 1.75 (3H, triplet); 4.70 (2H, multiplet); 5.0-5.7 (3H, multiplet).
11 ml of water and 0.10 g of camphorsulphonic acid were added to a solution of 0.70 g of methyl 5,6-epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17β-methyl-20-isopropylideneprost-13(E)-enoate in 30 ml of acetone, and the mixture was stirred for 1 hour at room temperature and then for 3 hours at 40° C. The mixture was then diluted with an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulphate. The solvent was then distilled from the extract under reduced pressure, giving 0.72 g of an oily residue. This residue was purified by column chromatography through 15 g of silica gel eluted with 200 ml each of a 50%, 60%, 70%, 80% and 90% mixture of ethyl acetate in hexane and with 100% ethyl acetate. 0.35 g of the title compound was obtained from the fractions eluted with 70-100% ethyl acetate in hexane.
Infrared Absorption Spectrum (liquid film) νmax cm-1 : 970, 1725, 3400.
Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 0.9 (3H, doublet); 3.64 (3H, singlet); 5.05 (1H, triplet); 5.47 (2H, multiplet).
The procedure of this example described above was repeated exactly, except that the camphorsulphonic acid was replaced by acetic acid. Deprotection of the protected hydroxy groups did not occur and the product was methyl 5,6-dihydroxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17β-methyl-20-isopropylideneprost-13(E)-enoate.
0.8 g of 5,6-epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17β-methyl-20-isopropylideneprost-13(E)-enoic acid [prepared as described in Example 1(b)] was dissolved in a mixture of methanol and ethyl acetate and then treated with 5% w/v hydrochloric acid. The resulting organic layer was separated, washed and dried over anhydrous sodium sulphate. The solvent was then distilled off under reduced pressure and the residue was purified by column chromatography through silica gel, to give 0.5 g of the title compound.
Infrared Absorption Spectrum (liquid film) νmax cm-1 : 1020, 1735, 3450.
0.22 g of 5,6-dihydroxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17β-methyl-20-isopropylideneprost-13(E)-enoic acid 1,5-lactone (prepared as described in Preparation 2) was dissolved in 10 ml of methanol. To this solution were added 50 mg of anhydrous potassium carbonate, and the mixture was stirred for 1 hour at room temperature. It was then diluted with water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulphate. The solvent was then distilled off under reduced pressure, giving 0.20 g of the title compound in the form of an oil.
Infrared Absorption Spectrum (liquid film) νmax cm-1 : 1020, 1740, 3460.
Hydrolysis of this ester with an alkali afforded the corresponding carboxylic acid.
0.30 g of methyl 5,6,11α,15α-tetrahydroxy-6,9α-methylene-17β-methyl-20-isopropylideneprost-13(E)-enoate (prepared as described in Preparation 1) was dissolved in 14 ml of a 4:2:1 by volume mixture of acetone, acetic acid and water. 0.17 g of sodium periodate was added to this solution, and the mixture was stirred for 1 hour at room temperature. It was then diluted with water and salted out. The resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulphate. The solvent was distilled off under reduced pressure, giving 0.27 g of an oily residue, which was purified by column chromatography through 7.5 g of silica gel, to give 0.15 g of the title compound as an oil.
Infrared Absorption Spectrum (liquid film) νmax cm-1 : 970, 1090, 1740, 3400.
Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 0.9 (3H, doublet); 5.1 (1H, triplet); 5.5 (2H, multiplet).
0.18 g of methyl 5,6-dihydroxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17β-methyl-20-isopropylideneprost-13(E)-enoate (prepared as described in Preparation 3) were dissolved in 10 ml of benzene. Lead tetraacetate was added to the solution and the mixture was stirred for 20 minutes at room temperature, after which an acetone solution of sodium iodide was added. The mixture was then washed with an aqueous solution of sodium thiosulphate and the organic layer was separated. This organic layer was washed with water and dried over sodium sulphate, after which the solvent was distilled off under reduced pressure, to give 0.17 g of an oily residue. This residue was purified by column chromatography through 10 g of silica gel eluted with 200 ml each of a 5%, 10%, 20% and 30% mixture of ethyl acetate in hexane. 0.117 g of the title compound was obtained from the fractions eluted with 20 and 30% ethyl acetate in hexane.
Infrared Absorption Spectrum (liquid film) νmax cm-1 : 970, 1020, 1030, 1130, 1742.
Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 0.9 (3H, multiplet); 4.68 (2H, multiplet); 5.1 (1H, triplet); 5.35-5.65 (2H, multiplet).
The procedures described in Preparations 1 and 4 were repeated, in turn, to give 0.30 g of the title compound from 0.88 g of methyl 5,6-epoxy-6,9α-methylene-11α,15α-diacetoxy-17β-methyl-20-isopropylideneprost-13(E)-enoate (prepared as described in Example 3).
Infrared Absorption Spectrum (liquid film) νmax cm-1 : 1240, 1735.
The procedures described in Preparations 1 and 4 were repeated in turn, to give 0.30 g of the title compound from 0.6 g of 5,6-epoxy-6,9α-methylene-11α,15α-dihydroxy-17β-methyl-20-isopropylideneprost-13(E)-enoic acid (prepared as described in Example 4).
Infrared Absorption Spectrum (liquid film) νmax cm-1 : 1733, 3380.
0.63 g of methyl 5,6-epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17β-methyl-20-isopropylideneprost-13(E)-enoate (prepared as described in Example 2) was dissolved in 10 ml of methanol. 4 ml of water and 55 mg of lithium hydroxide monohydrate were added to the solution, which was then stirred at 60° C. for 5 hours. At the end of this time, water and methanol were distilled off under reduced pressure and the residue was dissolved in benzene. From this, the water was removed by azeotropic distillation and the remaining solvent was distilled off under reduced pressure, to give 0.63 g of the title compound in the form of a glass.
Infrared Absorption Spectrum (Nujol-trade mark-mull) νmax cm-1 : 1020, 1580, 3380.
Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 4.7 (2H, multiplet); 5.0-5.7 (3H, multiplet).
Treatment of this lithium salt with dilute aqueous hydrochloric acid followed by conventional recovery procedures gave the corresponding free acid.
The procedure described in Preparation 5 was repeated, to give 0.37 g of the title compound from 0.54 g of lithium 5,6-dihydroxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17β-methyl-20-isopropylideneprost-13(E)-enoate (prepared as described in Preparation 8). The product had identical properties with the product of Preparation 5.
The procedure described in Preparation 8 was repeated except that twice the amount of base was used, to give 0.50 g of the title compound in the form of a glass from 0.51 g of 5,6-epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-15-cyclopentyl-16,17,18,19,20-pentanorprost-13(E)-enoic acid.
Infrared Absorption Spectrum (Nujol mull) νmax cm-1 : 1020, 1580, 3380.
Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 4.8 (2H, multiplet); 5.1-5.7 (2H, multiplet).
The procedure described in Preparation 8 was repeated, to give 0.72 g of the title compound in the form of a glass from 0.75 g of 5,6-epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)prost-13(E)-enoic acid (prepared as described in Example 5).
Infrared Absorption Spectrum (Nujol mull) νmax cm-1 : 1020, 1580, 3380.
Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 4.7 (2H, multiplet); 5.1-5.7 (2H, multiplet).
By following the procedure described in Preparation 8, lithium 5,6-dihydroxy-6,9α-methylene-11α,15α-bis-(2-tetrahydropyranyloxy)-20-methoxyprost-13(E)-enoate or lithium 5,6-dihydroxy-6,9α-methylene-11α,15α-bis-(2-tetrahydropyranyloxy)-16-methylprost-13(E)-en-18-ynoate were obtained from 5,6-epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-20-methoxyprost-13(E)-enoic acid (prepared as described in Example 6) or 5,6-epoxy-6,9α-methylene-11α,15α-bis-(2-tetrahydropyranyloxy)-16-methylprost-13(E)-en-18-ynoic acid (prepared as described in Example 7), respectively. Both lithium salts had the same infrared spectra.
Infrared Absorption Spectrum (Nujol mull) νmax cm-1 : 1020, 1580, 3380.
The procedure described in Preparation 8 was repeated, to give 0.34 g of the title compound in the form of a glass from 0.38 g of 5,6-epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-phenoxy-17,18,19,20-tetranorprost-13(E)-enoic acid (prepared as described in Example 9).
Infrared Absorption Spectrum (Nujol mull) νmax cm-1 : 1020, 1580, 3380.
Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 4.7 (2H, multiplet); 5.1-5.7 (2H, multiplet).
Claims (12)
1. Compounds of formula (I): ##STR20## in which: R1 and R2 are the same or different and each represents hydrogen or a hydroxy-protecting group;
R3 represents an alkyl group having from 1 to 12 carbon atoms which is optionally substituted, an alkenyl group having from 2 to 12 carbon atoms, an alkynyl group having from 2 to 6 carbon atoms or a cycloalkyl group which is optionally substituted; and
X represents an ethylene group, a trans-vinylene group or an ethynylene group
and salts and esters thereof.
2. Compounds as claimed in claim 1, wherein:
R1 and R2 are the same or different and each represents hydrogen or a hydroxy-protecting group;
R3 represents a C4 -C10 alkyl group which is unsubstituted or which has one or more fluorine, methoxy or ethoxy substituents; a C1 -C3 alkyl group having one or more cyclopentyl, 3-methylcyclopentyl, 3-ethylcyclopentyl, cyclohexyl, 3-methylcyclohexyl, 3-ethylcyclohexyl, phenyl, p-trifluoromethylphenoxy, phenoxy, phenylthio or p-tolyloxy substituents; a C4 -C12 alkenyl group; a C4 -C6 alkynyl group; cyclopentyl; 3-methylcyclopentyl; 3-ethylcyclopentyl; cyclohexyl; 3-methylcyclohexyl; or 3-ethylcyclohexyl; and
X represents an ethylene, trans-vinylene or ethynylene group;
and salts and aralkyl and C1 -C4 alkyl esters thereof.
3. Compounds as claimed in claim 2, wherein:
R1 and R2 are the same or different and each represents: hydrogen; a C1 -C4 alkyl group having at its α-position a C1 -C4 alkoxy, C1 -C4 alkylthio, aralkyloxy or trihalomethyl substituent; a 2-methoxyethoxymethyl group; a tetrahydrofuran-2-yl group; a tetrahydro-pyran-2-yl group; a 4-methoxytetrahydrothiopyran-4-yl group; a trialkylsilyl or dialkylphenylsilyl group, in which each alkyl group has from 1 to 4 carbon atoms; acetyl; propionyl; or benzoyl;
and salts and aralkyl and C1 -C4 alkyl esters thereof.
4. Compounds as claimed in claim 1, wherein:
R1 and R2 are the same or different and each represents a hydrogen atom or a methoxymethyl, tetrahydropyran-2-yl, t-butyl-dimethylsilyl, acetyl or benzoyl group;
R3 represents a pentyl, 1-methylpentyl, hexyl, 1-methylhexyl, 1,1-dimethylpentyl, 2-methylhexyl, 2-ethoxy-1,1-dimethylethyl, 5-methoxypentyl, 5-methoxy-1-methylpentyl, 1-fluoropentyl, cyclopentylmethyl, 3-methylcyclopentylmethyl, 2-cyclopentylethyl, 2-cyclopentyl-1-methylethyl, cyclohexylmethyl, 3-ethylcyclohexylmethyl, 2-cyclohexylethyl, benzyl, phenethyl, p-methyl-benzyl, phenoxymethyl, m-chlorophenoxymethyl, phenylthiomethyl, 2-pentenyl, 4-pentenyl, 4-hexenyl, 5-hexenyl, 6-methyl-5-heptenyl, 2,6-dimethyl-5-heptenyl, 3-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, cyclopentyl, 3-ethylcyclo-pentyl, cyclohexyl, 3-methylcyclohexyl or 1-butylcyclopropyl group; and
X represents an ethylene or trans-vinylene group;
and salts and methyl or ethyl esters thereof.
5. Compounds as claimed in claim 1, wherein:
R1 and R2 are the same or different and each represents a hydrogen atom, a tetrahydropyran-2-yl group, a t-butyl-dimethylsilyl group or an acetyl group;
R3 represents a pentyl, 1-methylhexyl, 1,1-dimethylpentyl, 5-methoxypentyl, phenoxymethyl, 2-pentenyl, 4-pentenyl, 4-hexenyl, 5-hexenyl, 6-methyl-5-heptenyl, 2,6-dimethyl-5-heptenyl, 1-methyl-3-pentynyl or cyclopentyl group; and
X represents a trans-vinylene group;
and salts and methyl esters thereof.
6. Compounds as claimed in claim 1 having the formula (Ia): ##STR21## wherein R1, R2, R3 and X are as defined in claim 1 and salts and esters thereof.
7. Compounds as claimed in claim 6, wherein:
R1 and R2 are the same or different and each represents a hydrogen atom, a tetrahydropyran-2-yl group, a t-butyl-dimethylsilyl group or an acetyl group;
R3 represents a pentyl, 1-methylhexyl, 1,1-dimethylpentyl, 5-methoxypentyl, phenoxymethyl, 2-pentenyl, 4-pentenyl, 4-hexenyl, 5-hexenyl, 6-methyl-5-heptenyl, 2,6-dimethyl-5-heptenyl, 1-methyl-3-pentynyl or cyclopentyl group; and
X represents a trans-vinylene group;
and salts and methyl esters thereof.
8. Compounds as claimed in claim 1 having the formula (Ib): ##STR22## wherein R1, R2, R3 and X are as defined in claim 1 and R4 represents hydrogen, C1 -C4 alkyl or aralkyl, and salts thereof.
9. Compounds as claimed in claim 8, wherein:
R1 and R2 are the same or different and each represents a hydrogen atom, a tetrahydropyran-2-yl group, a t-butyl-dimethylsilyl group or an acetyl group;
R3 represents a pentyl, 1-methylhexyl, 1,1-dimethylpentyl, 5-methoxypentyl, phenoxymethyl, 2-pentenyl, 4-pentenyl, 4-hexenyl, 5-hexenyl, 6-methyl-5-heptenyl, 2,6-dimethyl-5-heptenyl, 1-methyl-3-pentynyl or cyclopentyl group;
X represents a trans-vinylene group; and
R4 represents hydrogen or methyl;
and salts thereof.
10. Compounds as claimed in claim 1, selected from the group consisting of:
5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)prost-13(E)-enoic acid
5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydrofuranyloxy)prost-13-ynoic acid
5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-20-methylprost-13(E)-enoic acid
5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-17-methyl-20-isopropylideneprost-13(E)-enoic acid
5,6-Epoxy-6,9α-methylene-11α,15α-diacetoxy-17β-methyl-20-isopropylideneprost -13(E)-enoic acid
5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-15α-cyclopentyl-16,17,18,19,20-pentanorprost-13(E)-enoic acid
5. 6-Epoxy-6,9α-methylene-11α,15α-bis(t-butyl-dimethylsilyloxy)-15-cyclopentyl-16,17,18,19,20-pentanorprost-13(E)-enoic acid
5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxyprost-13(E)-enoic acid
5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxyprost-13-ynoic acid
5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16,16-dimethylprost-13(E)-enoic acid
5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-17β-methyl-20-isopropylideneprost-13(E)-enoic acid
5,6-Epoxy-6,9α-methylene-11α-(2-tetrahydropyranyloxy)-15α-hydroxy-17-methyl-20-isopropylideneprost-13(E)-enoic acid
5,6-Epoxy-6,9α-methylene-11α-(2-tetrahydro-pyranyloxy)-15.alpha.-(2-tetrahydrofuranyloxy)-17-methyl-20-isopropylideneprost-13(E)-enoic acid
5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-16-methylprost-13(E)-en-18-ynoic acid
5. 6-Epoxy-6,9α-methylene-11α-hydroxy-15α-(2-tetrahydropyranyloxy)-16-methylprost-13(E)-en-18-ynoic acid
5,6-Epoxy-6,9α-methylene-11α,15α-dihydroxy-15-cyclopentyl-16,17,18,19,20-pentanorprost-13(E)-enoic acid
and
5,6-Epoxy-6,9α-methylene-11α-(2-tetrahydropyranyloxy)-15α-hydroxy-15-cyclopentyl-16,17,18,19,20-pentanorprost-13(E)-enoic acid
5,6-Epoxy-6,9α-methylene-11α,15α-bis(2-tetrahydropyranyloxy)-16-methylprost-13(E)-en-18-ynoic acid
and sodium and potassium salts and methyl, ethyl and benzyl esters thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57/187760 | 1982-10-26 | ||
| JP57187760A JPS5978179A (en) | 1982-10-26 | 1982-10-26 | Epoxycarbacyclin derivative and its preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4496745A true US4496745A (en) | 1985-01-29 |
Family
ID=16211718
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US06/545,097 Expired - Fee Related US4496745A (en) | 1982-10-26 | 1983-10-25 | Epoxycarbacyclin derivatives, their preparation and use |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US4496745A (en) |
| JP (1) | JPS5978179A (en) |
| CH (1) | CH659472A5 (en) |
| DE (1) | DE3338832A1 (en) |
| FR (1) | FR2534917B1 (en) |
| GB (1) | GB2129001B (en) |
| IT (1) | IT1169903B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5257451A (en) * | 1991-11-08 | 1993-11-02 | Ep Technologies, Inc. | Method of making durable sleeve for enclosing a bendable electrode tip assembly |
| US5316766A (en) * | 1985-12-13 | 1994-05-31 | Schering Aktiengesellschaft | Thrombosis treatment with fibrinolytics and prostacyclins |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3811577A1 (en) * | 1988-03-31 | 1989-10-12 | Schering Ag | NEW METHOD FOR PRODUCING BICYCLO (3.3.0) OCTAN-3-ON DERIVATIVES |
| DE4034568A1 (en) * | 1990-10-26 | 1992-04-30 | Schering Ag | EPOXYCARBACYCLINE PREPARATIONS, THEIR PRODUCTION AND USE |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4322435A (en) * | 1978-01-06 | 1982-03-30 | Sankyo Company Limited | Prostacyclin compounds |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4110532A (en) * | 1977-07-14 | 1978-08-29 | The Upjohn Company | 5-Hydroxy-PGI1 compounds |
-
1982
- 1982-10-26 JP JP57187760A patent/JPS5978179A/en active Granted
-
1983
- 1983-10-25 US US06/545,097 patent/US4496745A/en not_active Expired - Fee Related
- 1983-10-26 DE DE19833338832 patent/DE3338832A1/en active Granted
- 1983-10-26 CH CH5808/83A patent/CH659472A5/en not_active IP Right Cessation
- 1983-10-26 GB GB08328614A patent/GB2129001B/en not_active Expired
- 1983-10-26 IT IT23472/83A patent/IT1169903B/en active
- 1983-10-26 FR FR8317103A patent/FR2534917B1/en not_active Expired
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4322435A (en) * | 1978-01-06 | 1982-03-30 | Sankyo Company Limited | Prostacyclin compounds |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5316766A (en) * | 1985-12-13 | 1994-05-31 | Schering Aktiengesellschaft | Thrombosis treatment with fibrinolytics and prostacyclins |
| US5257451A (en) * | 1991-11-08 | 1993-11-02 | Ep Technologies, Inc. | Method of making durable sleeve for enclosing a bendable electrode tip assembly |
Also Published As
| Publication number | Publication date |
|---|---|
| CH659472A5 (en) | 1987-01-30 |
| FR2534917A1 (en) | 1984-04-27 |
| DE3338832C2 (en) | 1991-10-02 |
| GB2129001A (en) | 1984-05-10 |
| JPH0352457B2 (en) | 1991-08-12 |
| GB2129001B (en) | 1985-10-02 |
| IT1169903B (en) | 1987-06-03 |
| GB8328614D0 (en) | 1983-11-30 |
| JPS5978179A (en) | 1984-05-04 |
| IT8323472A0 (en) | 1983-10-26 |
| FR2534917B1 (en) | 1987-04-17 |
| DE3338832A1 (en) | 1984-04-26 |
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